Bonviva

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

Composition:

Active substance: ibandronic acid;

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

The concentration of ibandronic acid in the injection solution is 1 mg/mL;

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

Pharmaceutical form. Solution for injection.

Main physicochemical properties: clear, colorless solution.

Pharmacotherapeutic group.

Agents affecting bone structure and mineralization. Bisphosphonates.

Ibandronic acid.

ATC code M05B A06.

Pharmacological Properties

Pharmacodynamics

Ibandronic acid is a highly active nitrogen-containing bisphosphonate that selectively acts on bone tissue and specifically inhibits osteoclast activity without directly affecting bone formation. The drug does not influence the process of replenishing 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 induced experimentally by gonadal function blockade, retinoids, tumors, and tumor extracts. In young (rapidly growing) rats, bone resorption was also observed, leading to an increase in 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 more than 5000 times the dose required for osteoporosis treatment.

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 when administered in the toxic range. The efficacy of daily and intermittent dosing of ibandronic acid with a 9–10 week interval between doses was confirmed in a clinical study (MF 4411) involving humans. In this study, ibandronic acid demonstrated efficacy in preventing fractures.

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

Daily and intermittent administration (with intervals between doses of 9–10 weeks, quarterly) of ibandronic acid orally or intravenously in postmenopausal women results in biochemical changes indicating dose-dependent inhibition of bone resorption.

Intravenous administration of Bonviva® leads to a reduction in serum levels of the C-telopeptide of type I collagen alpha chain 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 observed before treatment initiation occurs, reflecting increased bone resorption associated with postmenopausal osteoporosis.

Histological analysis of bone biopsy samples obtained after 2 and 3 years of treatment in postmenopausal women receiving oral ibandronic acid at a dose of 2.5 mg daily or intermittent intravenous doses up to 1 mg every 3 months showed normal bone tissue status. Furthermore, there was no evidence of impaired mineralization. After 2 years of treatment with Bonviva® injections at a dose of 3 mg, 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

After 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. About 85–87% binds to plasma proteins (determined in vitro using therapeutic concentrations of ibandronic acid), resulting in a low potential for interaction with other medicinal products due to displacement.

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 10–72 hours. Since calculated values depend significantly on study duration, administered dose, and assay sensitivity, the terminal half-life is likely considerably longer, similar to other bisphosphonates. Initial plasma levels 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 by bone tissue.

Secretion pathways likely do not involve known acidic or basic transport systems involved in the excretion of other active substances (see section "Interaction with other medicinal products and other forms of interaction"). Additionally, 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

Pharmacokinetic parameters of ibandronic acid are independent of gender.

Race

There are no data on clinically significant inter-ethnic 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 linearly dependent on creatinine clearance. Dose adjustment 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) receiving oral ibandronic acid at a dose of 10 mg 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 clearances were reduced by 67%, 77%, and 50%, respectively, in individuals with severe renal impairment, but no reduction in drug tolerability due to increased exposure was observed. Due to limited clinical experience with Bonviva®, its use is not recommended in patients with severe renal impairment (see sections "Posology and method of administration", "Special warnings and precautions for use"). Pharmacokinetics of ibandronic acid in patients with end-stage renal disease has been evaluated only in a small number of hemodialysis patients; thus, pharmacokinetics in non-dialyzed 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 through uptake by 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 independent of age. 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 forms of interaction.

Metabolic interactions are considered unlikely, since ibandronic acid does not inhibit 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.

Special precautions for use.

Administration errors

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

Hypocalcemia

Administration of Boniva®, as with other intravenously administered bisphosphonates, may lead to a temporary decrease in serum calcium levels. Hypocalcemia should be corrected prior to initiating treatment with Boniva®. All other disorders of bone metabolism and mineral imbalance should also be effectively managed. Adequate intake of calcium and vitamin D is recommended, as this is important for all patients.

Anaphylactic reaction/shock

Cases of anaphylactic reaction/shock, including fatal outcomes, have been observed in patients receiving intravenous ibandronate therapy.

Appropriate medical support and monitoring equipment must be readily available during intravenous administration of the drug. 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 the kidneys should undergo regular monitoring during treatment, in accordance with standard medical practice.

Due to limited clinical experience, Boniva® 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 "Dosage and administration", "Pharmacokinetics").

Heart failure

Excessive hydration should be avoided in patients at risk of developing heart failure.

Osteonecrosis of the jaw

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

The following risk factors should be considered when assessing the risk of developing osteonecrosis of the jaw:

• Potency of the bone resorption-inhibiting agent (higher risk with more 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, coagulopathies, infection), 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, invasive dental procedures such as tooth extraction.

During treatment with Boniva®, all patients should maintain good oral hygiene, undergo regular dental check-ups, and promptly report any oral symptoms such as tooth mobility, pain or swelling, non-healing ulcers, or discharge. Invasive dental procedures should only be performed after careful consideration and should be avoided during and shortly after Boniva® administration.

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 Boniva® therapy should be considered until improvement occurs 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. 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 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 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 before the fracture becomes 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. The decision to discontinue bisphosphonate therapy in patients with suspected atypical femoral fractures should be considered after a thorough patient assessment, taking into account the individual benefit-risk profile.

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

Sodium is not an ingredient of Boniva®.

Disposal of unused or expired medication: Environmental contamination should be minimized. The medication must not be disposed of via wastewater or household waste. Disposal should be carried out via a designated "waste collection system" where available.

Use during pregnancy or breastfeeding.

Pregnancy

Boniva® is indicated only for postmenopausal women. The drug 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 in humans is unknown. Boniva® should not be used during pregnancy.

Breastfeeding

It is unknown whether ibandronate passes into human breast milk. Studies have demonstrated low levels of ibandronate in the milk of lactating rats after intravenous administration. Boniva® should not be used during breastfeeding.

Fertility

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

Ability to influence reaction rate when driving or operating machinery.

Considering the pharmacodynamic characteristics, pharmacokinetic profile, and reported adverse reactions, Boniva® is expected to have no or 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 drug is intended for intravenous use only (see "Special Warnings and Precautions for Use").

Patients should additionally receive calcium and vitamin D supplements (see sections "Special Warnings and Precautions for Use", "Interaction with Other Medicinal Products and Other Forms of Interaction").

If a scheduled dose is missed, the injection should be administered as soon as possible. Subsequent injections should be given every 3 months starting 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, taking into account the individual benefit and potential risks of Bonviva® for each patient, especially after 5 or more years of treatment.

Special Patient Groups

Patients with Renal Impairment

Bonviva® injections are not recommended for 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 "Special Warnings and Precautions for Use", "Pharmacokinetics").

Dose adjustment is not required in patients with mild or moderate renal impairment, with 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").

Children

There is insufficient experience regarding the use of Bonviva® in children (under 18 years of age). The use of Bonviva® in children (under 18 years of age) has not been studied (see sections "Pharmacodynamics", "Pharmacokinetics").

Special Instructions for Use

If the medicinal product is administered through an existing intravenous infusion system, the infusion solution 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 release of the medicinal product should be minimized.

Strict adherence to the following instructions is required for the use and disposal of syringes and other sharp instruments:

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

Children

There is insufficient experience regarding the use of Bonviva® in children (under 18 years of age). The use of Bonviva® in children (under 18 years of age) has not been studied (see sections "Pharmacodynamics", "Pharmacokinetics").

Overdose

There is no specific information on the treatment of Bonviva® overdose.

Based on available 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.

Side effects

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 selected adverse reactions" and section "Special warnings and precautions for use").

The most commonly reported adverse reactions were arthralgia and flu-like symptoms. These symptoms were usually associated with the first dose, were generally transient, mild to moderate in severity, and typically resolved with continued treatment and did not require medical intervention (see "Description of selected adverse reactions").

Below is a complete list of known adverse reactions.

The safety of ibandronic acid 2.5 mg daily orally has been evaluated in 1,251 patients participating 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 Bonviva® administered as 3 mg intravenous injections every 3 months and for 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 Bonviva® 3 mg intravenous injection every 3 months, respectively. In most cases, adverse reactions did not lead to discontinuation of treatment.

Adverse reactions listed below are classified according to MedDRA terminology by system organ class and frequency categories. Frequencies are defined as: 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 not known (cannot be estimated from 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 Bonviva® 3 mg intravenous injection every 3 months or oral ibandronic acid 2.5 mg daily, and during post-marketing use.

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

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)†. Osteoarthritis, joint function disorders.

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

*See below.

†Identified during post-marketing use.

Description of selected adverse reactions

Flu-like illness

Flu-like illness included symptoms such as acute phase reactions, 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.

Ocular inflammation

Inflammatory eye disorders such as uveitis, episkleritis, and scleritis have been reported with ibandronic acid use. 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.

Shelf life.

2 years.

Storage conditions.

Store out of reach and sight of children at a temperature not exceeding 30°C.

Incompatibilities.

Bonviva® must not be mixed with calcium-containing solutions or with other medicinal products for intravenous use.

Packaging.

3 ml of solution in a pre-filled syringe.

One pre-filled syringe with one sterile injection needle, placed in a plastic container, packed in a cardboard box labelled in Ukrainian.

Prescription category.

Prescription only.

Manufacturer.

Roche Diagnostics GmbH
Weimberg PL

Manufacturer's location and address of place of business.

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