Bondronat

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT BONDRONAT® (BONDRONAT®)

Composition:

Active substance: ibandronic acid;

1 vial (6 ml) of the medicinal product contains 6 mg of ibandronic acid in the form of sodium ibandronate monohydrate 6.750 mg;

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

Pharmaceutical form. Concentrate for solution for infusion.

Main physicochemical properties: colourless transparent solution.

Pharmacotherapeutic group. Agents used in the treatment of bone diseases. Agents affecting bone structure and mineralization. Bisphosphonates. Ibandronic acid.

ATC code M05BA06.

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 exact mechanism is still unknown.

In vivo, ibandronic acid prevents bone destruction induced experimentally by gonadal function blockade, retinoids, tumors, and tumor extracts. Inhibition of endogenous bone resorption has also been documented in 45Ca kinetic studies and by measuring the release of previously administered radiolabeled tetracycline.

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

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, reducing bone resorption and thereby decreasing skeletal complications of malignancy.

Pharmacokinetics.

After 2-hour infusion at doses of 2, 4, 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 penetrates into and accumulates in bone tissue. At therapeutic concentrations, about 87% is bound to plasma proteins; therefore, due to displacement, the potential for interaction with other medicinal products is low.

Metabolism.

There are no data available 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 from 10 to 60 hours. However, initial plasma levels of the drug decline rapidly, reaching 10% of peak values within 3 hours and 8 hours after intravenous and oral administration, respectively. With intravenous administration of ibandronic acid at 4-week intervals over 48 weeks in patients with bone metastases, 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 uptake of the drug by bone tissue.

The excretion pathways apparently do not involve known acid or base 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 situations.

Gender.

Bioavailability and pharmacokinetic parameters of ibandronic acid are independent of gender.

Race.

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

Patients with renal impairment.

Exposure to ibandronic acid in patients with various stages of renal impairment is related to 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 (AUC0–24h) increased by 110% compared to healthy volunteers. In the clinical pharmacology study WP18551, after a single 6 mg intravenous dose (15-minute infusion), the mean AUC0–24h increased by 14% and 86% in patients with mild (mean creatinine clearance – 68.1 mL/min) and moderate renal impairment (mean creatinine clearance – 41.2 mL/min), respectively, compared to healthy volunteers (mean creatinine clearance – 120 mL/min). Mean Cmax did not increase in patients with mild renal impairment and increased by 12% in patients with moderate renal impairment. Dose adjustment is not required for patients with mild renal impairment (creatinine clearance ≥ 50 and < 80 mL/min). 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 is eliminated via the kidneys and 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 moderate (approximately 87%), it is unlikely that hypoalbuminemia in severe liver disease would lead to a clinically significant increase in free drug concentration.

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

Multivariate analysis has shown that pharmacokinetic parameters are independent of patient age. Since renal function declines with age, this is the only factor that needs to be considered (see section "Patients with renal impairment").

Children (see section "Dosage and administration").

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

Clinical characteristics.

Indications.

• Prevention of skeletal events (pathological fractures, bone lesions requiring radiation therapy or surgical intervention) in patients with breast cancer and metastatic bone involvement.
• Treatment of hypercalcemia of malignancy 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 types of interactions.

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

Bisphosphonates should be used with caution in combination with aminoglycosides, as both substances may reduce serum calcium levels for a prolonged period. Also, when these drugs are used concomitantly, hypomagnesemia should be considered.

Special precautions for use.

Patients with impaired bone and mineral metabolism

Hypocalcemia and other disturbances of bone metabolism and mineral metabolism should be corrected prior to initiating treatment with Bondrone® 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 in the form of dietary supplements should be considered.

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. If an anaphylactic or other severe hypersensitivity/allergic reaction occurs, the infusion should be stopped immediately and appropriate treatment initiated.

Osteonecrosis of the jaw

Osteonecrosis of the jaw has been reported very rarely during post-marketing use in patients receiving Bondrone® for oncological indications (see section "Adverse reactions").

Initiation or re-initiation of treatment should be delayed in patients with non-healing open soft tissue lesions in the oral cavity. Prior to starting treatment with Bondrone®, patients with concomitant risk factors should undergo a dental examination, including preventive dental interventions, and an individual benefit-risk assessment should be performed.

Factors to consider when evaluating the risk of developing osteonecrosis of the jaw include:

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

During treatment with Bondrone®, 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, swelling, or non-healing ulcers or discharge. Invasive dental procedures should only be performed after careful consideration during treatment and should be avoided during and for some time after treatment with Bondrone®. Management of patients who develop osteonecrosis of the jaw should be coordinated in close collaboration with a physician, dentist, or oral and maxillofacial surgeon experienced in treating this condition. Temporary interruption of Bondrone® therapy should be considered 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 include corticosteroid and chemotherapy use 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, primarily 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 region. These fractures typically occur after minimal or no trauma, and some patients report thigh or groin pain, often associated with characteristic features of a stress fracture, for several weeks to months before the fracture becomes complete. Fractures are often bilateral; therefore, the contralateral femur should also be evaluated in patients receiving bisphosphonates who have sustained a femoral shaft fracture. Poor healing of these fractures has also been reported. Discontinuation of bisphosphonate therapy should be considered in patients with suspected atypical femoral fractures pending full evaluation, with individual assessment of benefit versus risk.

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

Renal impairment

Clinical studies have not shown evidence of renal dysfunction with long-term treatment with Bondrone®. However, during treatment with Bondrone®, monitoring of renal function and serum levels of calcium, phosphorus, and magnesium is recommended based on clinical assessment of each patient (see section "Dosage and administration").

Hepatic impairment

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

Heart failure

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

Patients with hypersensitivity to other bisphosphonates

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

Excipients with known effect

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

Disposal of unused medicine and expired products: Medicinal waste should be minimized from entering the environment. The medicine should 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 rat studies. The potential risk in humans is unknown. Bondrone® should not be used during pregnancy.

Breastfeeding

It is unknown whether ibandronic acid passes into human breast milk. Studies in lactating rats have shown low levels of ibandronic acid in milk after intravenous administration. Bondrone® should not be used during breastfeeding.

Fertility

There are no data on the effect of ibandronic acid in humans. In reproductive studies in rats, ibandronic acid reduced fertility at high daily doses administered orally or intravenously.

Ability to influence the speed of reactions when driving or operating machinery

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

Method of Administration and Dosage

Treatment with Bondronat® should only be prescribed by a physician experienced in the management of malignant tumors.

Dosage

Prevention of Skeletal Events 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 preparation is administered intravenously as an infusion over at least 15 minutes, once every 3–4 weeks.

A shorter (i.e., 15-minute) infusion duration 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 below 50 mL/min. Physicians should refer to the section "Special Patient Populations. Patients with Renal Impairment" for dosage and administration recommendations for these patient groups.

Treatment of Hypercalcemia of Malignancy

Treatment with Bondronat® should only be initiated after adequate hydration with 0.9% sodium chloride solution (9 mg/mL). The dose 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. For patients with moderate hypercalcemia (albumin-corrected serum calcium < 3 mmol/L or < 12 mg/dL), a dose of 2 mg is effective. The highest dose used in clinical trials was 6 mg; however, administration of this dose does 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 albumin-corrected serum 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 albumin-corrected serum calcium concentration above 3 mmol/L) was 18–19 days with 2 mg and 4 mg doses. 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 drug may be considered in cases of recurrent hypercalcemia or inadequate response.

Bondronat® 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

Dose adjustment is not required in patients with mild renal impairment (creatinine clearance ≥ 50 and < 80 mL/min).

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 recommendations should 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

10.9% sodium chloride solution or 5% glucose solution.

2Administration once every 3–4 weeks.

The duration of drug administration over 15 minutes has not been studied in patients with malignant tumors and creatinine clearance less than 50 mL/min.

Elderly patients (> 65 years of age)

Dosage adjustment in elderly patients 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. Bonfronat**®** must be administered only as an intravenous infusion. Bonfronat**®** must not be administered intraarterially or paravenously, as this may lead to tissue damage.

From a microbiological standpoint, the preparation should be used immediately. If not used immediately, storage time and conditions of the prepared solution are the responsibility of the user, provided that dilution was carried out under controlled and validated aseptic conditions. The prepared solution may be stored for no more than 24 hours at 2–8°C.

Children

Safety and efficacy of Bonfronat® in children under 18 years of age have not been established. No data are available.

Overdose

There are no data on acute overdose with Bonfronat**®**, concentrate for infusion solution. Due to potential hepatotoxic and nephrotoxic effects observed in preclinical studies at high doses, organ function should be monitored. In case of hypocalcemia, treatment with intravenous calcium gluconate should be administered.

Adverse Reactions

Summary of Safety Profile

The most serious adverse reactions reported include anaphylactic reaction/shock, atypical femoral fractures, osteonecrosis of the jaw, and ocular inflammation (see "Description of Specific Adverse Reactions" and section "Special Warnings and Precautions for Use").

Treatment of malignancy-associated hypercalcemia was most frequently associated with fever. Hypocalcemia (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.

Prophylactic use for skeletal events in patients with breast cancer and bone metastases was most frequently associated with asthenia and accompanied by fever and headache.

Below are the adverse reactions observed in pivotal phase III clinical trials (treatment of malignancy-induced hypercalcemia: 311 patients received Bonviva® at a dose of 2 or 4 mg; prevention of skeletal events in patients with breast cancer and bone metastases: 152 patients receiving Bonviva® 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) system organ classes and frequency categories. Adverse reactions are categorized by frequency 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), and frequency not known (cannot be estimated from available data). Within each frequency category, reactions are listed in decreasing order of severity.

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

Benign, malignant and unspecified neoplasms (tumors): uncommon – benign skin neoplasms.

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

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

Endocrine disorders: common – disorders of parathyroid gland.

Metabolism and nutrition disorders: common – hypocalcemia**; uncommon – hypophosphatemia.

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

Nervous system disorders: common – headache, dizziness, dysgeusia (altered taste); uncommon – cerebrovascular disorders, nerve root disorder, amnesia, migraine, neuralgia, hypertension, hyperesthesia, perioral paresthesia, parosmia.

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

Ear and labyrinth disorders: uncommon – deafness.

Cardiac disorders: common – bundle branch block; uncommon – myocardial ischemia, cardiovascular disorders, palpitations.

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

Gastrointestinal disorders: common – diarrhea, 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, ecchymosis; 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 characteristic of bisphosphonates as a class)†.

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 (fever), influenza-like illness**, peripheral edema, asthenia, thirst; uncommon – hypothermia.

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

Injury, poisoning and procedural complications: uncommon – injury, injection site pain.

**See below for detailed information.

†Identified during post-marketing use.

Description of Specific Adverse Reactions

Hypocalcemia

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

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.

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 conditions resolved only after discontinuation of ibandronic acid.

Anaphylactic reaction/shock

Anaphylactic reactions/shock, including fatal cases, have been observed in patients receiving intravenous ibandronic acid.

Reporting of Suspected Adverse Reactions

Reporting suspected adverse reactions after marketing authorization 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 national pharmacovigilance system.

Shelf Life

5 years.

Storage Conditions

Keep out of reach and sight of children. Store at temperatures not exceeding 30 °C.

Reconstituted (diluted) infusion solutions of Bonviva® are stable for 24 hours at 2–8 °C (in a refrigerator), provided that dilution was performed under aseptic conditions.

Incompatibilities

To avoid incompatibility, Bonviva® should be diluted only in 0.9% sodium chloride isotonic solution or 5% glucose solution.

Bonviva® must not be mixed with solutions containing calcium.

Packaging

6 ml of concentrate for infusion solution in a 6 ml colorless glass vial with a fluoropolymer-laminated rubber stopper and an aluminum cap with a tear-off plastic disk. One vial per carton.

Prescription Category

Prescription only.

Manufacturer

Roche Diagnostics GmbH
Weymouth PLS

Manufacturer's Address and Place of Business

Sandhofer Strasse 116, 68305 Mannheim, Germany
Sovereign House, Miles Gray Road, Basildon, SS14 3FR, United Kingdom