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

Composition:

Active substance: ibandronic acid;

One film-coated tablet contains 50 mg of ibandronic acid in the form of 56.25 mg of sodium ibandronate monohydrate;

Excipients: povidone K25; lactose monohydrate; microcrystalline cellulose; crospovidone; stearic acid 95; colloidal anhydrous silicon dioxide;

Film coating: Opadry 00A28646 (hypromellose, titanium dioxide (E171), talc), macrogol 6000.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: elongated white or almost white film-coated tablets, engraved with "L2" on one side and "IT" on the other side.

Pharmacotherapeutic group.

Agents affecting bone structure and mineralization. Bisphosphonates. Ibandronic acid.

ATC code M05BA06.

Pharmacological Properties

Pharmacodynamics

Ibandronic acid is a bisphosphonate that specifically acts on bone tissue. It exerts a selective effect on bone 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 by measuring the release of pre-administered radioactive tetracycline into bone tissue.

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

Bone tissue resorption associated with malignant disease 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.

In clinical studies in patients with breast cancer and bone metastases, a dose-dependent inhibitory effect on bone osteolysis has been demonstrated, as determined by bone resorption markers, along with a dose-dependent effect on skeletal events.

Pharmacokinetics

Absorption.

After oral administration, ibandronic acid is rapidly absorbed in the upper gastrointestinal tract. Time to maximum plasma concentration is 0.5–2 hours (median 1 hour) after fasting administration, with absolute bioavailability of approximately 0.6%. Absorption is impaired when administered with food or beverages (other than plain water). Bioavailability decreases by approximately 90% when taken with a standard breakfast compared to administration on an empty stomach. When ibandronic acid is taken 30 minutes before food intake, bioavailability decreases by approximately 30%. No significant reduction in bioavailability is observed when ibandronic acid is taken 60 minutes before food intake.

Bioavailability decreases by approximately 75% when Bondrone® tablets are administered 2 hours after a standard meal. Therefore, Bondrone® tablets should be taken in the morning (after at least 6 hours without food intake) and the patient should remain fasting for at least 30 minutes after taking Bondrone® (see section "Directions for Use and Dosage").

Distribution.

Following initial systemic exposure, ibandronic acid rapidly binds to bone tissue or is excreted via urine. In humans, the apparent volume of distribution is at least 90 L, and approximately 40–50% of the circulating drug penetrates and accumulates in bone tissue. At therapeutic concentrations, about 87% is bound to plasma proteins, resulting in a low potential for interaction with other medicinal products due to displacement.

Metabolism.

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

Excretion.

The absorbed portion of ibandronic acid is removed from the bloodstream either by bone uptake (approximately 40–50%) or excreted unchanged by the kidneys. The non-absorbed portion is excreted unchanged in feces. The apparent elimination half-life range is wide and depends on the administered dose and assay sensitivity; however, the apparent terminal half-life ranges from 10 to 60 hours. However, initial plasma levels of the drug decline rapidly, reaching 10% of peak levels within 3 hours and 8 hours after intravenous administration or 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 drug uptake by bone tissue.

Excretion pathways apparently 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 Situations

Sex.

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

Race.

There are no data on 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 correlated with creatinine clearance. In patients with severe renal impairment (creatinine clearance ≤30 mL/min) receiving oral ibandronic acid 10 mg for 21 days, plasma concentrations were 2–3 times higher than in patients with normal renal function (creatinine clearance ≥80 mL/min). Total clearance of ibandronic acid was reduced to 44 mL/min in patients with severe renal impairment compared to 129 mL/min in those with normal renal function. Dose adjustment is not required for patients with mild renal impairment (creatinine clearance ≥50 mL/min and <80 mL/min). Dose adjustment is recommended for patients with moderate renal impairment (creatinine clearance ≥30 to <50 mL/min) and severe renal impairment (creatinine clearance <30 mL/min) (see section "Directions for Use and Dosage").

Patients with Hepatic Impairment (see section "Directions for Use and Dosage").

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 is excreted by the kidneys and through uptake into bone tissue. Therefore, dose adjustment is not required in patients with hepatic impairment. Since protein binding of ibandronic acid at therapeutic concentrations to plasma proteins is low (approximately 87%), it is unlikely that hypoalbuminemia in severe liver disease would lead to a clinically significant increase in free drug concentration.

Advanced Age (see section "Directions for Use and Dosage").

Pharmacokinetic parameters studied 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 "Directions for Use and Dosage").

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

Clinical characteristics.

Indications.

Prevention of skeletal events (pathological fractures, bone complications requiring radiation therapy or surgical intervention) in patients with breast cancer and metastatic bone involvement.

Contraindications.

Hypersensitivity to ibandronic acid or to any other component of the medicinal product (see section "Composition"). Hypocalcemia. Esophageal disorders with delayed emptying of the esophagus, such as stricture or achalasia. Inability to remain in an upright position (standing or sitting) for at least 60 minutes.

Interaction with other medicinal products and other forms of interaction.

Interaction of the medicinal product with food

Foods containing calcium, including milk, and other polyvalent cations (aluminum, magnesium, iron) may interfere with the absorption of Bondrone® tablets. Therefore, such foods and food products should be consumed at least 30 minutes after oral administration of Bondrone®.

Bioavailability was reduced by approximately 75% when Bondrone® tablets were administered 2 hours after a standard meal. Therefore, Bondrone® should be taken in the morning (after at least 6 hours of fasting) and fasting should be continued for 30 minutes after administration of Bondrone® (see section "Dosage and administration").

Interaction with other medicinal products

Metabolic interactions are unlikely, as 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 does not undergo biotransformation.

H2-receptor antagonists and other medicinal products increasing gastric pH

In a study involving healthy volunteers (men) and postmenopausal women, intravenous ranitidine increased the bioavailability of ibandronic acid by approximately 20% (within the normal variability of ibandronic acid bioavailability), possibly due to reduced gastric acidity. However, dose adjustment of Bondrone® is not required when co-administered with H2-receptor antagonists or other agents that increase gastric pH.

Acetylsalicylic acid and nonsteroidal anti-inflammatory drugs (NSAIDs)

Since acetylsalicylic acid, NSAIDs, and bisphosphonates may cause gastrointestinal irritation, caution should be exercised when administering NSAIDs concomitantly with Bondrone® (see section "Special precautions for use").

Aminoglycosides

Bisphosphonates should be used with caution in combination with aminoglycosides, as both substances may reduce serum calcium levels over a prolonged period. Hypomagnesemia should also be monitored when these agents are used concomitantly.

Special precautions for use.

Patients with impaired bone and mineral metabolism

Hypocalcemia and other disturbances of bone tissue and mineral metabolism should be corrected prior to initiating treatment with Bonviva®. 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.

Gastrointestinal tract irritation

Oral bisphosphonates may cause local irritation of the upper gastrointestinal mucosa. Due to these potential effects and the possibility of worsening underlying gastrointestinal conditions, caution is required when administering Bonviva® to patients with active upper gastrointestinal disorders (Barrett’s esophagus, dysphagia, other esophageal diseases, gastritis, duodenitis, peptic ulcers).

Cases of adverse reactions such as esophagitis, esophageal ulcers, and esophageal erosions have been reported with oral bisphosphonates. Some of these cases were severe, requiring hospitalization, and rarely were associated with bleeding or subsequent development of strictures or perforation. The risk of developing severe esophageal adverse reactions is higher in patients who do not follow dosing instructions and/or continue taking oral bisphosphonates after developing symptoms indicative of esophageal irritation. Therefore, patients must strictly adhere to the dosing recommendations (see section "Dosage and administration").

Physicians should remain vigilant for any signs or symptoms suggesting possible esophageal reaction or irritation and should inform patients of the necessity to discontinue Bonviva® and consult a physician if dysphagia, pain upon swallowing, retrosternal pain, heartburn, or worsening heartburn occurs.

Although no increased risk was observed in controlled clinical trials, post-marketing use of oral bisphosphonates has reported cases of gastric and duodenal ulcers. Some of these were severe and associated with complications.

Acetylsalicylic acid and nonsteroidal anti-inflammatory drugs (NSAIDs)

Since acetylsalicylic acid, NSAIDs, and bisphosphonates may all cause gastrointestinal irritation, concomitant use of these medicinal products with Bonviva® should be undertaken with caution.

Osteonecrosis of the jaw (ONJ)

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

The following risk factors should be considered when evaluating 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, and invasive dental procedures such as tooth extraction.

During treatment with Bonviva®, 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, non-healing ulcers, or discharge. Invasive dental procedures should only be performed after careful consideration and should be avoided shortly after initiating Bonviva®.

Management of patients who develop osteonecrosis of the jaw should be planned in close collaboration with a dentist or oral and maxillofacial surgeon experienced in managing ONJ. Temporary discontinuation of Bonviva® 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. 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 just above the supracondylar region. These fractures typically occur after minimal or no trauma, and some patients experience thigh or groin pain, often associated with features typical of stress fractures, for several weeks to months prior to a complete 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 possibility of discontinuing bisphosphonate therapy should be considered in patients with suspected atypical femoral fractures, pending full evaluation and 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 function impairment with long-term Bonviva® therapy. However, during treatment with Bonviva®, renal function, as well as serum calcium, phosphorus, and magnesium levels, should be monitored according to clinical assessment of each patient.

Rare hereditary disorders

The product contains lactose. Patients with rare hereditary disorders such as galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicine.

Patients with hypersensitivity to other bisphosphonates

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

Disposal of unused or expired medication: Environmental contamination should be minimized. Medicinal products must not be disposed of via wastewater or household waste. Disposal should be carried out via an established "waste collection system" where 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 to humans is unknown. Bonviva® should not be used during pregnancy.

Breastfeeding

It is unknown whether ibandronic acid is excreted in human breast milk. Studies in lactating rats have shown low levels of ibandronic acid in milk after intravenous administration. Bonviva® 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 when administered orally or intravenously at high daily doses.

Ability to influence reaction speed when driving or operating machinery.

Considering the pharmacodynamic and pharmacokinetic profile and reported adverse reactions, Bonviva® is expected to have no or 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 diseases.

Dosage

The recommended dose is 1 tablet (50 mg) once daily.

The tablets should be taken orally in the morning (after at least 6 hours of fasting) and before consuming any food or drink on that day. Similarly, other medicinal products and dietary supplements (including calcium) should be avoided until after administration of Bondronat® tablets. Food should also be avoided for at least 30 minutes after taking Bondronat® tablets. Plain water may be consumed at any time during Bondronat® therapy (see section "Interaction with other medicinal products and other forms of interaction"). Water with a high calcium concentration should not be consumed. If there is concern about potentially high calcium levels in drinking water (hard water), it is recommended to use bottled water with a low mineral content.

The tablets should be swallowed whole, without chewing, with a glass of plain water (180–240 mL), while in an upright position (sitting or standing).

Patients should remain in an upright position for 60 minutes after taking Bondronat®.

The tablets should not be chewed, sucked, or crushed due to the risk of developing ulcers in the oropharyngeal mucosa.

Bondronat**®** should be taken only with plain water.

Special dosage recommendations

Patients with hepatic impairment

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

Patients with renal impairment

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

For patients with moderate renal impairment (creatinine clearance ≥30 mL/min and <50 mL/min), the recommended dose is 1 tablet of 50 mg every two days (see section "Pharmacokinetics in special situations").

For patients with severe renal impairment (creatinine clearance <30 mL/min), the recommended dose is 1 tablet of 50 mg once weekly.

Elderly patients

Dose adjustment in elderly patients is not required (see section "Pharmacokinetics in special situations").

Children

The safety and efficacy of Bondronat® have not been established in children under 18 years of age. No data are available (see sections "Method of administration and dosage" and "Pharmacokinetics in special situations").

Overdose

There is no specific information regarding the treatment of Bondronat® overdose. However, in cases of oral overdose, gastrointestinal reactions such as gastrointestinal disturbances, heartburn, esophagitis, gastritis, or ulceration may occur. To bind Bondronat®, milk or antacids should be administered. Due to the risk of esophageal irritation, vomiting should not be induced. Patients should remain in an upright position.

Adverse Reactions

Summary of safety profile

The most serious adverse reactions reported are anaphylactic reaction/shock, atypical femoral fractures, osteonecrosis of the jaw, gastrointestinal irritation, and ocular inflammation (see "Description of individual adverse reactions" and section "Special warnings and precautions for use"). The most common adverse reaction associated with treatment was hypocalcaemia, defined as serum calcium levels below the normal range. The next most frequent adverse reaction was dyspepsia.

The adverse reactions listed below were observed in two pivotal phase III clinical trials (prevention of skeletal events in patients with breast cancer and bone metastases: 286 patients treated with Bondrone**®** 50 mg orally), as well as those reported during post-marketing use.

Adverse reactions are listed below according to MedDRA (Medical Dictionary for Regulatory Activities) system organ class and frequency categories. Frequencies are defined as follows: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10,000 to <1/1000), very rare (<1/10,000), and frequency not known (cannot be estimated from available data). Within each frequency group, adverse reactions are listed in order of decreasing severity.

Blood and lymphatic system disorders: uncommon – anaemia.

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

Metabolism and nutrition disorders: common – hypocalcaemia**.

Nervous system disorders: uncommon – paraesthesia (taste disturbance).

Eye disorders: rare – ocular inflammation†**.

Gastrointestinal disorders: common – oesophagitis, abdominal pain, dyspepsia, nausea; uncommon – haemorrhage, duodenal ulcer, gastritis, dysphagia, dry mouth.

Skin and subcutaneous tissue disorders: uncommon – pruritus; very rare – Stevens-Johnson syndrome†, erythema multiforme†, bullous dermatitis†.

Musculoskeletal and connective tissue disorders: 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 – azotaemia (uraemia).

General disorders and administration site conditions: common – asthenia; uncommon – chest pain, influenza-like syndrome, malaise, pain.

Investigations: uncommon – increased serum parathyroid hormone levels.

** See below for detailed information.

† Identified during post-marketing use.

Description of individual 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 levels consistent with hypocalcaemia.

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

Ocular inflammatory events 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

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

Shelf life.

5 years.

Storage conditions.

Keep out of reach and sight of children. Store below 30°C in a dry place.

Packaging.

7 tablets in a blister pack, 4 blisters in a cardboard carton.

Prescription status.

Prescription only.

Manufacturer.

F. Hoffmann-La Roche Ltd

Welwyn Place, United Kingdom

Manufacturer's address and location of operations.

Grenzacherstrasse 124, 4070 Basel, Switzerland

Sovereign House, Miles Gray Road, Basildon, SS14 3FR, United Kingdom