Bonevista

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

Composition:

Active substance: ibandronic acid;

1 pre-filled syringe (3 ml solution) contains 3 mg of ibandronic acid in the form of sodium ibandronate monohydrate 3.375 mg;

the concentration of ibandronic acid in the injectable solution is 1 mg/ml;

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

Pharmaceutical form. Solution for injection.

Main physicochemical properties: clear, almost particle-free, colorless solution in a transparent colorless glass syringe with a plunger, plunger rod, cap, and needle.

Pharmacotherapeutic group.

Agents affecting bone structure and mineralization. Bisphosphonates. Ibandronic acid. ATC code M05BA06.

Pharmacological properties.

Pharmacodynamics.

Ibandronic acid is a highly active nitrogen-containing bisphosphonate that acts selectively on bone tissue and specifically inhibits osteoclast activity without directly affecting bone formation. The medicinal product BonViva does not influence the replenishment of the osteoclast pool. In postmenopausal women, it reduces the elevated rate of bone turnover to premenopausal levels, resulting in progressive increases in bone mass and a reduction in fracture frequency.

Ibandronic acid inhibits bone resorption. In vivo, ibandronic acid prevents bone destruction caused experimentally by gonadal function blockade, retinoids, tumors, and tumor extracts. In young (rapidly growing) rats, increased bone resorption was observed, leading to a higher normal bone mass compared to untreated animals. Animal models confirm that ibandronic acid is a highly potent inhibitor of osteoclast activity. In growing rats, no signs of impaired mineralization were observed even at doses exceeding the osteoporosis treatment dose by more than 5000 times.

Long-term daily administration and intermittent administration (with long intervals) over prolonged periods in rats, dogs, and monkeys were associated with the formation of new bone of normal quality, with preserved or increased mechanical strength, even at doses within the toxic range. The efficacy of daily and intermittent administration of ibandronic acid with dosing intervals of 9–10 weeks was confirmed in a clinical study (MF 4411) involving humans, in which ibandronic acid demonstrated effectiveness in preventing fractures.

In animal models, ibandronic acid induces biochemical changes indicating dose-dependent inhibition of bone tissue resorption, including reduced levels of urinary biochemical markers of bone collagen degradation (deoxypyridinoline, cross-linked N-telopeptide of type I collagen).

Daily and intermittent (with dosing intervals of 9–10 weeks, quarterly) oral or intravenous administration of ibandronic acid in postmenopausal women leads to biochemical changes indicating dose-dependent inhibition of bone resorption.

Intravenous administration of ibandronic acid results in a reduction of serum C-telopeptide of the alpha chain of type I collagen within 3–7 days after initiation of treatment and a reduction in osteocalcin levels within 3 months.

After discontinuation of treatment, a return to pathological levels of increased bone resorption associated with postmenopausal osteoporosis, observed prior to treatment initiation, is noted.

Histological analysis of bone biopsy samples obtained after 2 and 3 years of treatment in postmenopausal women receiving oral ibandronic acid at a daily dose of 2.5 mg and intermittent intravenous administration up to 1 mg every 3 months showed normal bone tissue status. Furthermore, no evidence of mineralization defects was found. After 2 years of treatment with 3 mg injections of ibandronic acid, the expected reduction in bone metabolism was observed, along with normal bone tissue quality and absence of mineralization defects.

Pharmacokinetics.

The primary pharmacological effect of ibandronic acid on bone is not directly related to actual plasma concentrations of ibandronic acid, as demonstrated in various studies in animals and humans.

Plasma concentrations of ibandronic acid increase proportionally with dose following intravenous administration of 0.5–6 mg.

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 BonViva drug substance penetrates and accumulates in bone tissue. Approximately 85–87% is bound to plasma proteins (determined in vitro at therapeutic concentrations of ibandronic acid); therefore, due to displacement, the potential for interaction with other medicinal products is low.

Metabolism.

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

Elimination.

Ibandronic acid is eliminated from the bloodstream via bone uptake (approximately 40–50% in postmenopausal women), with the remainder excreted unchanged by the kidneys.

The range of apparent elimination half-life is broad, varying between 10 and 72 hours. Since calculated values depend significantly on study duration, administered dose, analytical method sensitivity, the terminal elimination half-life is likely considerably longer, as seen with other bisphosphonates. Initial plasma levels of BonViva decline rapidly, reaching 10% of peak values within 3 hours and 8 hours after intravenous and oral administration, respectively.

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 BonViva by bone tissue.

Excretion pathways likely do not involve known acidic or basic transport systems involved in the elimination of other active substances (see section "Interaction with other medicinal products and other types of interactions"). Additionally, ibandronic acid does not inhibit major human hepatic P450 isoenzymes and does not induce the cytochrome P450 system in rats.

Pharmacokinetics in special situations.

Sex.

Pharmacokinetic parameters of ibandronic acid are not influenced by sex.

Race.

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

Patients with renal impairment.

Renal clearance of ibandronic acid in patients with various stages of renal impairment is linearly dependent on creatinine clearance. Dose adjustment of BonViva is not required in patients with mild to moderate renal impairment (creatinine clearance ≥ 30 mL/min).

In individuals with severe renal impairment (creatinine clearance < 30 mL/min) who received 10 mg oral ibandronic acid for 21 days, plasma concentrations were 2–3 times higher than in individuals with normal renal function, and total clearance of ibandronic acid was 44 mL/min. After intravenous administration of 0.5 mg ibandronic acid, total, renal, and non-renal clearance decreased by 67%, 77%, and 50%, respectively, in individuals with severe renal impairment; however, no reduction in BonViva tolerability due to increased exposure was observed. Due to limited clinical experience with ibandronic acid, it is not recommended in patients with severe renal impairment (see sections "Special precautions for use" and "Posology and method of administration"). Pharmacokinetics of ibandronic acid in patients with end-stage renal disease has been evaluated only in a small number of hemodialysis patients; therefore, pharmacokinetics in non-dialysis patients is unknown. Due to limited data, ibandronic acid should not be used in patients with end-stage renal disease.

Patients with hepatic impairment (see section "Posology and method of administration"). There are no data on the pharmacokinetics of ibandronic acid in patients with hepatic impairment. The liver does not play a significant role in the clearance of ibandronic acid, which is not metabolized but excreted by the kidneys and via uptake into bone tissue. Therefore, dose adjustment is not required in patients with hepatic impairment.

Elderly patients (see section "Posology and method of administration").

Pharmacokinetic parameters studied in multivariate analysis are not age-dependent. Since renal function decreases with age, this is the only factor to consider (see section "Patients with renal impairment").

Paediatric population (see section "Posology and method of administration").

There are no data on the use of BonViva in children.

Clinical characteristics.

Indications.

Treatment of osteoporosis in postmenopausal women with increased risk of fractures. Reduction in the risk of vertebral fractures has been demonstrated; efficacy in preventing hip fractures has not been established.

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 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 excreted via renal elimination and is not subject to biotransformation processes.

Special precautions for use.

Administration errors.

Caution must be exercised to avoid intra-arterial or paravenous administration of Bonviva, as this may lead to tissue damage.

Hypocalcemia.

The use of Bonviva, as with other intravenously administered bisphosphonates, may cause a temporary decrease in serum calcium levels. Hypocalcemia should be corrected prior to initiating Bonviva therapy. All other disorders of bone metabolism and mineral homeostasis should also be effectively managed. Adequate intake of calcium and vitamin D should be ensured, as this is important for all patients.

Anaphylactic reaction/shock.

Anaphylactic reactions/shock, including fatal cases, have been reported in patients receiving intravenous ibandronate. Appropriate medical support and monitoring equipment must be readily available during intravenous administration of Bonviva. If an anaphylactic or other severe hypersensitivity/allergic reaction occurs, the infusion must be stopped immediately and appropriate treatment initiated.

Renal impairment.

Patients with concomitant diseases or those taking medications that may adversely affect renal function should undergo regular monitoring during treatment, in accordance with standard medical practice.

Due to limited clinical experience, ibandronate injections are not recommended for patients with serum creatinine levels exceeding 200 µmol/L (2.3 mg/dL) or creatinine clearance below 30 mL/min (see sections «Pharmacokinetics» and «Posology and method of administration»).

Heart failure.

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

Osteonecrosis of the jaw.

Osteonecrosis of the jaw has been reported very rarely during post-marketing use in patients receiving ibandronate for osteoporosis (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 Bonviva therapy, patients with concomitant risk factors should undergo a dental examination with appropriate preventive dental procedures and an individual benefit-risk assessment.

When evaluating the risk of osteonecrosis of the jaw, the following risk factors should be considered:

• 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 therapy;
• Malignant neoplasms, concomitant medical conditions (e.g., anemia, coagulopathy, infection), tobacco smoking;
• Concomitant therapy: corticosteroids, chemotherapy, angiogenesis inhibitors, radiotherapy to the head and neck region;
• Poor oral hygiene, periodontal disease, ill-fitting dentures, dental history, invasive dental procedures such as tooth extractions.

During treatment with Bonviva, all patients should maintain good oral hygiene, undergo regular dental check-ups, and promptly report any oral symptoms such as tooth mobility, pain, swelling, non-healing ulcers, or discharge. Invasive dental procedures should only be performed after careful consideration and should be avoided during and shortly after Bonviva treatment. Management of patients who develop osteonecrosis of the jaw should be planned in close collaboration with a dentist or an oral and maxillofacial surgeon experienced in treating osteonecrosis of the jaw. Temporary discontinuation of Bonviva therapy should be considered until condition improves and contributing 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. Risk factors include corticosteroid and chemotherapy use and/or local risk factors such as infection or trauma. 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 osteoporosis treatment. 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 after 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 before the fracture manifests as a complete femoral fracture. Fractures are often bilateral; therefore, the contralateral femur should also be examined in patients receiving bisphosphonate therapy who have sustained a femoral shaft fracture. Poor healing of these fractures has also been reported. The possibility of discontinuing bisphosphonate therapy should be considered in patients with suspected atypical femoral fractures after a full assessment of individual benefit-risk.

During bisphosphonate treatment, patients should be advised to report any new thigh, hip, or groin pain; all patients with such symptoms should be evaluated for an 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 after minor trauma or without trauma, and some patients experience prodromal pain before a complete fracture is diagnosed. In cases of ulnar fracture, this may be associated with repetitive stress due to prolonged use of walking aids (see section «Adverse reactions»).

Disposal of unused medicine and waste: Medicinal product should not be disposed of via wastewater or household waste. To minimize environmental contamination, unused or expired medication should be disposed of via a designated waste collection system, if available.

Important information on excipients.

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

Use during pregnancy or breastfeeding.

Pregnancy.

Bonviva is indicated only for postmenopausal women and should not be used in women of reproductive age. There are no adequate data on the use of ibandronate in pregnant women. Reproductive toxicity was observed in rat studies. The potential risk to humans is unknown. Bonviva should not be used during pregnancy.

Breastfeeding.

It is unknown whether ibandronate passes into breast milk. Studies in lactating rats have shown low levels of ibandronate in milk after intravenous administration. Bonviva should not be used during breastfeeding.

Fertility.

There are no data on the effect of ibandronate in humans. In reproductive studies in rats, oral ibandronate reduced fertility at high daily doses.

Effects on ability to drive and use machines.

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

Method of Administration and Dosage

Dosage.

The recommended dose of ibandronic acid is 3 mg administered as an intravenous injection over 15–30 seconds every 3 months. The medicinal product is intended for intravenous use only (see section "Special Warnings and Precautions for Use").

Patients should receive additional calcium and vitamin D supplementation (see sections "Interaction with Other Medicinal Products and Other Forms of Interaction" and "Special Warnings and Precautions for Use"). If a scheduled dose is missed, administration of BonVista should be performed as soon as possible. Subsequently, injections should continue every 3 months from the date of the last administration.

The optimal duration of bisphosphonate treatment for osteoporosis has not been established. The need for continued treatment should be periodically reassessed based on the individual benefit-risk balance for each patient, particularly after 5 or more years of treatment with BonVista.

Special Patient Groups.

Patients with Renal Impairment.

BonVista injections are not recommended in patients with serum creatinine levels exceeding 200 µmol/L (2.3 mg/dL) or creatinine clearance (measured or calculated) below 30 mL/min, due to limited clinical data in this patient group (see sections "Pharmacokinetics" and "Special Warnings and Precautions for Use"). Dose adjustment is not required in patients with mild to moderate renal impairment, defined as serum creatinine levels ≤200 µmol/L (2.3 mg/dL) or creatinine clearance (measured or calculated) ≥30 mL/min.

Patients with Hepatic Impairment.

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

Elderly Patients (>65 years).

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

Special Instructions for Use

When the medicinal product is administered through an existing intravenous infusion system, the infusion fluid must be either isotonic saline or 5% glucose solution (50 mg/mL). This also applies to solutions used for flushing the catheter and other devices.

Any unused injection solution, syringes, and injection needles must be disposed of in accordance with local requirements. Environmental contamination with the medicinal product should be minimized.

The following instructions for use and disposal of syringes and other sharp instruments must be strictly observed:

• Needles and syringes must never be reused.
• All used needles and syringes must be placed in a sharps container (puncture-resistant, single-use container).
• The sharps container must be kept out of reach of children.
• The sharps container must not be disposed of in household waste.
• The filled container must be disposed of in accordance with local regulations or as instructed by the physician.

Children.

There is insufficient experience with the use of BonVista in children under 18 years of age. The use of BonVista has not been studied in children under 18 years of age (see sections "Pharmacodynamics" and "Pharmacokinetics").

Overdose.

Symptoms. Based on current knowledge of bisphosphonates, overdose following intravenous administration may lead to hypocalcemia, hypophosphatemia, and hypomagnesemia. Clinically significant reductions in serum calcium, phosphate, and magnesium levels should be corrected by intravenous administration of calcium gluconate, potassium or sodium phosphate, and magnesium sulfate, respectively.

Treatment. There is no specific information available on the treatment of overdose with BonVista.

Adverse reactions.

Summary of safety profile.

The most serious adverse reactions reported are anaphylactic reaction/shock, atypical femoral fractures, osteonecrosis of the jaw, and ocular inflammation (see "Description of individual adverse reactions" and section "Special warnings and precautions for use").

The most commonly reported adverse reactions were arthralgia and influenza-like symptoms. These symptoms were generally associated with the first dose, were usually transient, mild to moderate in severity, and typically resolved with continued treatment without requiring medical intervention (see "Description of individual adverse reactions").

Below is a complete list of known adverse reactions.

The safety of ibandronic acid administered at a dose of 2.5 mg once daily orally was evaluated in 1251 patients who participated in four placebo-controlled clinical trials, with the majority of patients enrolled in the pivotal three-year fracture study (MF 4411).

In the pivotal two-year study in postmenopausal women with osteoporosis (VM 16550), the overall safety profile was similar for intravenous ibandronic acid 3 mg every 3 months and oral ibandronic acid 2.5 mg daily. The total proportion of patients experiencing an adverse reaction was 26.0% and 28.6% after one and two years of treatment with intravenous ibandronic acid 3 mg every 3 months, respectively. In most cases, adverse reactions did not lead to discontinuation of treatment. Adverse reactions are listed below according to the Medical Dictionary for Regulatory Activities (MedDRA) system organ class and frequency categories. Adverse reactions are categorized by frequency as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10000 to < 1/1000), very rare (< 1/10000), and not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are listed in order of decreasing severity.

Adverse reactions observed during Phase III studies VM16550 and MF4411 in postmenopausal women receiving intravenous ibandronic acid 3 mg every 3 months or oral ibandronic acid 2.5 mg daily, and during post-marketing use.

Immune system disorders: uncommon – exacerbation of bronchial asthma; rare – hypersensitivity reactions; very rare – anaphylactic reaction/shock*†.

Metabolism and nutrition disorders: uncommon – hypocalcaemia.

Nervous system disorders: common – headache.

Eye disorders: rare – ocular inflammation*†.

Vascular disorders: uncommon – phlebitis/thrombophlebitis.

Gastrointestinal disorders: common – gastritis, dyspepsia, diarrhoea, abdominal pain, nausea, constipation.

Skin and subcutaneous tissue disorders: common – rash; rare – angioneurotic oedema, facial swelling/oedema, urticaria; very rare – Stevens-Johnson syndrome†, erythema multiforme†, bullous dermatitis†.

Musculoskeletal and connective tissue disorders: common – arthralgia, myalgia, musculoskeletal pain, back pain; uncommon – 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)†; frequency not known – atypical fractures of long bones other than the femur.

General disorders and administration site conditions: common – influenza-like illness*, fatigue; uncommon – administration site reactions, asthenia.

*See below.

†Identified during post-marketing use.

Description of individual adverse reactions.

Influenza-like illness.

Influenza-like illness included symptoms such as acute phase reactions or symptoms, including myalgia, arthralgia, fever, chills, fatigue, nausea, loss of appetite, and bone pain.

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 treatment, 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, including uveitis, episkleritis, and scleritis, have been reported with the use of ibandronic acid. In some cases, these inflammatory conditions 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 authorization of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, or their legal representatives, are encouraged to report all suspected adverse reactions and lack of efficacy through the Automated Information System for Pharmacovigilance at the following link: https://aisf.dec.gov.ua

Shelf life.

2 years.

Storage conditions.

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

Incompatibilities.

The medicinal product Bonivista must not be mixed with calcium-containing solutions or with other medicinal products intended for intravenous administration.

Packaging.

3 ml in a pre-filled syringe, 1 pre-filled syringe with needle in a blister pack, 1 blister pack in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Synthon España, S.L.

Manufacturer's address and place of business.

C/Castello, no1, Sant Boi de Llobregat, Barcelona, 08830, Spain.