Bonapur

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT BONAPUR (BONAPUR)

Composition:

Active substance: ibandronic acid;

One film-coated tablet contains 150 mg of ibandronic acid in the form of sodium ibandronate monohydrate 168.79 mg;

Excipients: povidone, microcrystalline cellulose, pregelatinized starch, crospovidone (type A), colloidal anhydrous silicon dioxide, glycerol dibehenate;

Film coating: hypromellose 15 cP; hypromellose 3 cP; hypromellose 50 cP; titanium dioxide (E 171); macrogol; lactose monohydrate.

Pharmaceutical form. Film-coated tablets.

Main physico-chemical properties: white, round, biconvex tablets with dimensions: 11.2 mm ± 0.1 mm – diameter and 5.0 mm ± 0.2 mm – thickness.

Pharmacotherapeutic group.

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

Pharmacological properties

Pharmacodynamics

Ibandronic acid is a highly potent nitrogen-containing bisphosphonate that acts selectively on bone tissue and specifically inhibits osteoclast activity without having a direct effect on bone formation. The drug does not affect 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, reduced bone resorption was observed, leading to increased 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 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 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 fracture occurrence.

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

In a Phase I bioequivalence study involving 72 postmenopausal women, subjects received 150 mg orally every 28 days (a total of 4 doses). In this study, a reduction in serum concentration of cross-linked C-telopeptide of type I collagen (CTX) was observed within the first 24 hours after the first dose (on average by 28%), with the mean maximum reduction (by 69%) observed on day 6. After the third and fourth doses, the mean maximum reduction by day 6 after each dose was 74%, and 28 days after the fourth dose, the mean reduction in concentration was 56%. Upon discontinuation of further drug administration, the reduction in biochemical markers of bone resorption ceases.

Clinical efficacy

To identify women at increased risk of osteoporotic fractures, the following risk factors should be considered: low bone mineral density (BMD), age, history of prior fractures, family history of fractures, and body mass index. Ibandronic acid at a dose of 150 mg once monthly

Bone mineral density (BMD)

Treatment with ibandronic acid 150 mg once monthly has been shown to be at least as effective as ibandronic acid 2.5 mg daily in increasing BMD over a two-year, double-blind, multicenter study (BM 16549) in postmenopausal women with osteoporosis (lumbar spine BMD T-score below -2.5 SD at baseline). This was demonstrated in both the primary one-year analysis and the confirmatory two-year endpoint analysis (see Table 1).

Table 1

Mean relative change from baseline after one year (primary analysis) and two years of treatment (per protocol population) in study BM 16549

In addition, the advantages of using ibandronic acid 150 mg once monthly compared to ibandronic acid 2.5 mg daily have been demonstrated in terms of increasing lumbar spine BMD in a prospectively planned analysis at one year (p=0.002) and at two years (p<0.001).

At one year (primary analysis), lumbar spine BMD was increased or returned to baseline levels in 91.3% (p=0.005) of patients receiving ibandronic acid 150 mg once monthly, compared to 84.0% of patients receiving 2.5 mg ibandronic acid daily.

Total hip BMD was increased or returned to baseline levels in 90% (p<0.001) of patients receiving ibandronic acid 150 mg once monthly and in 76.7% of patients receiving 2.5 mg ibandronic acid daily at one year. At two years, total hip BMD was increased or returned to baseline levels in 93.4% (p<0.001) of patients receiving ibandronic acid 150 mg once monthly and in 78.4% of patients receiving 2.5 mg ibandronic acid daily.

When considering a more stringent criterion combining both lumbar spine and total hip BMD, 83.9% (p<0.001) and 65.7% of patients receiving ibandronic acid 150 mg once monthly or 2.5 mg daily, respectively, met this criterion after one year. At two years, 87.1% (p<0.001) and 70.5% of patients met this criterion in the groups receiving ibandronic acid 150 mg once monthly and 2.5 mg daily, respectively.

Biochemical markers of bone turnover.

Clinically significant reductions in serum beta-C-terminal telopeptide (CTX) levels were observed at all measured time points—i.e., at 3, 6, 12, and 24 months. At one year (primary analysis), the median relative change from baseline was -76% for ibandronic acid 150 mg once monthly and -67% for ibandronic acid 2.5 mg daily. At two years, the median relative change was -68% and -62% in the groups receiving 150 mg monthly and 2.5 mg daily, respectively.

At one year, 83.5% (p=0.006) of patients receiving ibandronic acid 150 mg once monthly and 73.9% of patients receiving ibandronic acid 2.5 mg daily were classified as responders (defined as a decrease of ≥50% from baseline). At two years, 78.7% (p=0.002) and 65.6% of patients were classified as responders in the 150 mg monthly and 2.5 mg daily groups, respectively. Based on the results of study BM 16549, ibandronic acid 150 mg once monthly is expected to be at least as effective in preventing fractures as ibandronic acid 2.5 mg daily.

Ibandronic acid 2.5 mg daily.

In the initial three-year, randomized, double-blind, placebo-controlled fracture study (MF 4411), a statistically and clinically significant reduction in the incidence of new radiographic morphometric and clinical vertebral fractures was demonstrated (see Table 2). In this study, ibandronic acid was evaluated at oral doses of 2.5 mg daily and 20 mg intermittently as the investigational regimen. Ibandronic acid was administered at least 60 minutes before the first food or beverage of the day (dosing interval after dose). The study included women aged 55 to 80 years who had been postmenopausal for at least 5 years, had a lumbar spine BMD (T-score) at least 2–2.5 SD below the premenopausal mean at one or more vertebrae [L1–L4], and had 1–4 prevalent vertebral fractures. All patients received 500 mg calcium and 400 IU vitamin D daily. Efficacy was evaluated in 2928 patients. Administration of ibandronic acid 2.5 mg daily resulted in a statistically and clinically significant reduction in the incidence of new vertebral fractures. This regimen reduced the number of new radiographic vertebral fractures by 62% (p=0.0001) over the three-year study period. After 2 years, a relative risk reduction of 61% (p=0.0006) was observed. A statistically significant difference was not achieved after 1 year of treatment (p=0.056). There was no evidence of a decrease in effect over time. The incidence of clinical vertebral fractures was also significantly reduced—by 49% (p=0.011). Furthermore, a significant effect on vertebral fractures was demonstrated by a statistically significant reduction in height loss compared to placebo (p<0.0001).

Table 2

Results from the three-year fracture study MF 4411 (%; 95% CI)

The therapeutic effect of ibandronic acid was further evaluated in a subpopulation analysis of patients with a baseline lumbar spine BMD T-score below -2.5. The reduction in vertebral fracture risk closely corresponded to that observed in the overall population.

Table 3

Results of the 3-year fracture study MF 4411 (%; 95% CI) for patients with lumbar spine BMD T-score below -2.5 at baseline

In the overall patient population in the MF 4411 study, a reduction in non-vertebral fractures was not observed; however, daily administration of ibandronic acid was effective in a high-risk subpopulation (femoral neck BMD <-3.0), where a 69% reduction in vertebral fracture risk was observed.

Daily administration of 2.5 mg ibandronic acid led to progressive increases in BMD at vertebral and non-vertebral skeletal sites.

A clinically significant 50% reduction in biochemical markers of bone resorption was observed as early as one month after initiation of treatment with 2.5 mg ibandronic acid daily. After discontinuation of treatment, a return to pathological levels of increased bone resorption associated with postmenopausal osteoporosis was observed. Histological analysis of bone biopsies after two and three years of treatment in postmenopausal women showed normally structured bone morphology and indicated no mineralization defect.

Pediatric population. The use of ibandronic acid has not been studied in the pediatric population, and therefore there are no data on efficacy and safety of the drug in this patient group.

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.

Absorption.

After oral administration, ibandronic acid is rapidly absorbed in the upper gastrointestinal tract. Plasma concentrations increase proportionally with dose increases up to 50 mg orally, and more than proportionally with further dose increases. Maximum plasma concentration is reached within 30 minutes to 2 hours (on average, 1 hour) when administered on an empty stomach; absolute bioavailability is approximately 0.6%. Absorption is impaired when administered with food or drink (other than plain water). Bioavailability is reduced by approximately 90% when administered with a standard breakfast compared to administration on an empty stomach. No significant reduction in bioavailability occurs if ibandronic acid is taken 60 minutes before the first intake of food. Intake of food or beverages less than 60 minutes after administration of ibandronic acid reduces both bioavailability and bone mineral density gains.

Distribution.

Following initial systemic distribution, ibandronic acid rapidly binds to bone tissue or is excreted in urine. In humans, the apparent volume of distribution is at least 90 L; approximately 40–50% of the drug circulating in blood penetrates and accumulates in bone tissue. Approximately 85–87% is bound to plasma proteins (determined in vitro at therapeutic concentrations of ibandronic acid), resulting in a low potential for interaction with other drugs 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 in urine. The portion of ibandronic acid that is not absorbed is excreted unchanged in feces.

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, and assay sensitivity, the terminal elimination half-life is likely considerably longer, as is the case with other bisphosphonates. Initial plasma levels of the drug decrease rapidly, reaching 10% of peak values 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 uptake of the drug by bone tissue. Secretion pathways likely do not involve known acidic or basic transport systems involved in the excretion of other active substances. Furthermore, ibandronic acid does not inhibit major human hepatic P450 isoenzymes and does not induce the cytochrome P450 system in rats.

Pharmacokinetics in special populations.

Gender.

Bioavailability and pharmacokinetic parameters of ibandronic acid are 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), as demonstrated in study BM16549, in which most patients had mild to moderate renal impairment.

In patients with severe renal impairment (creatinine clearance <30 mL/min) receiving 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 were reduced by 67%, 77%, and 50%, respectively, in patients with severe renal impairment; however, no reduction in drug tolerability due to increased exposure was observed. Due to limited clinical experience with the drug, its use is not recommended in patients with severe renal impairment (see sections "Special precautions", "Dosage and administration"). Pharmacokinetics of ibandronic acid in patients with end-stage renal disease has been evaluated only in a small number of patients on hemodialysis; therefore, the pharmacokinetics in non-dialysis patients are unknown. Due to limited data, ibandronic acid should not be used in patients with end-stage renal disease.

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 does not play a significant role in the clearance of ibandronic acid, which is not metabolized but is excreted via the kidneys and bone uptake. Therefore, dose adjustment is not required in patients with hepatic impairment.

Elderly patients (see sections "Dosage and administration"). Pharmacokinetic parameters evaluated in multivariate analysis are independent of age. Since renal function declines with age, this is the only factor to consider (see section "Patients with renal impairment").

Children (see section "Dosage and administration").

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

Clinical characteristics.

Indications.

Treatment of osteoporosis in postmenopausal women at 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.

Hypocalcemia.

Esophageal disorders that delay esophageal emptying, such as stricture or achalasia.

Inability to remain in an upright position (sitting or standing) for at least 60 minutes.

Interaction with other medicinal products and other forms of interaction.

Medicinal product - food interaction.

The oral bioavailability of ibandronic acid is generally reduced when administered with food. In particular, food products containing calcium, including milk, and other polyvalent cations (aluminum, magnesium, iron) may interfere with drug absorption, consistent with findings from animal studies. Therefore, the medicinal product should be taken after an overnight fast (at least 6 hours) and fasting should be continued for 1 hour after administration (see section "Dosage and administration").

Interaction with other medicinal products.

Metabolic interactions are considered 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 excreted via the kidneys and is not subject to biotransformation.

Calcium preparations, antacids, and certain other medicinal products containing polyvalent cations. Calcium supplements, antacids, and certain other oral medicinal products containing polyvalent cations (aluminum, magnesium, iron) may interfere with drug absorption. Therefore, patients should not take other medicinal products at least 6 hours before and 1 hour after taking this medicinal product.

Acetylsalicylic acid and NSAIDs.

Since acetylsalicylic acid, nonsteroidal anti-inflammatory drugs (NSAIDs), and bisphosphonates may cause gastrointestinal irritation, concomitant use of NSAIDs with this medicinal product should be done with caution (see section "Special warnings and precautions for use").

H2-blockers and proton pump inhibitors.

In study BM16549 involving 1500 patients, dosing regimens of ibandronic acid (daily and once monthly) were compared, with 14% and 18% of patients receiving H2-receptor blockers or proton pump inhibitors at one and two years, respectively. The incidence of upper gastrointestinal events in patients receiving the 150 mg once-monthly dose was similar to that in patients receiving 2.5 mg daily ibandronic acid. In a study involving healthy volunteers (men) and postmenopausal women, intravenous ranitidine increased the bioavailability of ibandronic acid by approximately 20%, possibly due to reduced gastric acidity. However, since this increase falls within the normal range of ibandronic acid bioavailability, dosage adjustment of the medicinal product is not required when co-administered with H2-receptor blockers or other agents that increase gastric pH.

Special precautions for use.

Hypocalcemia.

Hypocalcemia should be corrected prior to initiating treatment with the medicinal product. All other disorders of bone metabolism and mineral metabolism should also be effectively treated. Adequate intake of calcium and vitamin D should be ensured, as this is important for all patients.

Gastrointestinal irritation.

Oral bisphosphonates may cause local irritation of the mucosa of the upper gastrointestinal tract.

Due to these potential effects and the possibility of worsening the underlying disease, caution is required when administering the medicinal product to patients with active upper gastrointestinal disorders (Barrett's esophagus, dysphagia, other esophageal diseases, gastritis, duodenitis, or peptic ulcers). Cases of adverse reactions such as esophagitis, esophageal ulcers, and esophageal erosions have been reported with oral bisphosphonate use, some of which were severe and required hospitalization, and rarely involved 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 recommendations and/or in individuals who continue taking oral bisphosphonates after developing symptoms indicative of esophageal irritation. Therefore, patients must pay particular attention to following the dosing instructions (see section "Dosage and administration").

Physicians should be vigilant for symptoms suggesting possible esophageal reactions and should inform patients to discontinue the medicinal product and seek medical advice if symptoms such as dysphagia, pain on swallowing, retrosternal pain, new or worsening heartburn occur. Although no increased risk was observed in controlled clinical trials, cases of gastric and duodenal ulcers have been reported during post-marketing use of oral bisphosphonates. Some of these were severe and complicated. Since nonsteroidal anti-inflammatory drugs (NSAIDs) and bisphosphonates may both cause gastrointestinal irritation, concomitant use of NSAIDs with this medicinal product should be done with caution.

Osteonecrosis of the jaw.

Osteonecrosis of the jaw has been reported very rarely during post-marketing use in patients receiving the medicinal product for osteoporosis (see section "Adverse reactions").

Initiation or re-initiation of treatment should be delayed in patients with unhealed open soft tissue lesions in the oral cavity.

Prior to starting treatment, patients with concomitant risk factors are recommended to undergo a dental examination with appropriate preventive interventions and individual benefit-risk assessment.

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

• Potency of the medicinal product inhibiting bone resorption (risk is higher with highly potent compounds), route of administration (risk is higher with parenteral administration), and cumulative dose of bone-resorbing therapy.
• Malignant neoplasms, concomitant pathological 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, history of dental disease, invasive dental procedures such as tooth extraction.

During treatment, all patients should maintain good oral hygiene, undergo regular dental examinations, 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 during treatment and should be avoided during and shortly after administration of the medicinal product.

Management of patients who develop osteonecrosis of the jaw should be planned in close collaboration between the physician and a dentist or oral and maxillofacial surgeon experienced in treating osteonecrosis of the jaw. Consideration should be given to temporarily discontinuing the medicinal product until improvement in condition and reduction of concomitant risk factors.

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 for osteonecrosis of the external auditory canal include steroid 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 during bisphosphonate treatment, particularly in patients receiving long-term therapy 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 ridge. These fractures occur after minimal or no trauma, and some patients experience thigh or groin pain, often associated with characteristic features of stress fractures, several weeks to months before the fracture manifests as a complete femoral fracture. Fractures are often bilateral; therefore, the contralateral femur should also be evaluated in patients receiving bisphosphonate therapy who have developed a femoral shaft fracture. Poor healing of these fractures has also been reported. Pending patient evaluation, including individual benefit-risk assessment, consideration should be given to discontinuing bisphosphonate therapy in patients with suspected atypical femoral fractures.

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 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 the fracture becomes apparent as a complete fracture. In cases of ulnar fracture, this may be related to repetitive stress from prolonged use of walking aids (see section "Adverse reactions").

Renal impairment.

Due to limited clinical experience, the medicinal product is not recommended for patients with creatinine clearance below 30 mL/min (see section "Pharmacokinetics").

Important information on excipients.

Lactose.

If intolerance to certain sugars has been diagnosed, consult a physician before taking this medicinal product.

Disposal of unused medicinal product or expired medicinal product. Environmental contamination should be minimized. The medicinal product 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. The medicinal product is intended for use only in postmenopausal women. It should not be used in women of reproductive age. There are insufficient data on the use of ibandronic acid in pregnant women. Reproductive toxicity was observed in rat studies. The potential risk in humans is unknown. The medicinal product should not be used during pregnancy.

Breastfeeding. It is unknown whether ibandronic acid is excreted in human breast milk. Studies in lactating rats have demonstrated low levels of ibandronic acid in milk after intravenous administration. The medicinal product should not be used during breastfeeding.

Fertility. There are no data on the effect of ibandronic acid in humans. In reproductive studies in rats, oral administration of ibandronic acid reduced fertility.

Ability to influence reaction speed when driving or operating machinery.

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

Method of Administration and Dosage

Dosage

For the treatment of osteoporosis, the recommended dose is 1 tablet of 150 mg once a month, administered orally. Tablets should be taken on the same day each month. The medicinal product should be taken after an overnight fast (at least 6 hours) and 60 minutes before the first intake of food, beverages (other than water), or other oral medicinal products or supplements (including calcium) in the day (see section "Interaction with other medicinal products and other forms of interaction").

Patients should be informed that if a monthly dose is missed, they should take 1 tablet of 150 mg the following morning as soon as they remember, provided that the day of the next scheduled dose is not within 7 days. Subsequent doses should be taken on the previously established day of the month. If the next scheduled dose is due within 7 days, the missed dose should be skipped, and the next dose should be taken on the planned day of the month, continuing with one tablet per month on the previously established day. Two tablets should not be taken within one week. Patients should ensure adequate intake of calcium and/or vitamin D if dietary intake is inadequate (see sections "Interaction with other medicinal products and other forms of interaction", "Special precautions").

The optimal duration of treatment with bisphosphonates for osteoporosis has not been established. The need for continued treatment should be periodically reviewed for each individual patient, taking into account the benefits and potential risks of the medicinal product, particularly after 5 or more years of treatment.

Special Patient Groups

Patients with renal impairment. Due to limited clinical experience, the medicinal product is not recommended for patients with creatinine clearance below 30 ml/min (see sections "Pharmacokinetics", "Special precautions"). Dose adjustment is not required in patients with mild to moderate renal impairment if creatinine clearance is equal to or exceeds 30 ml/min.

Patients with hepatic impairment. Dose adjustment is not required (see section "Pharmacokinetics").

Elderly patients (> 65 years of age). Dose adjustment is not required (see section "Pharmacokinetics").

Children. There is no appropriate experience with the use of this medicinal product in children under 18 years of age.

Method of Administration

• Tablets should be swallowed whole with one glass of plain water (180–240 ml), while sitting or standing in an upright position. Water with high calcium concentration should not be used. If there are concerns about potentially high calcium levels in drinking water (hard water), it is recommended to use bottled water with low mineral content.
• Patients should remain upright (sitting or standing) for at least 60 minutes after taking the tablet.
• Tablets should be taken only with plain water.
• Patients should not chew or suck the tablet due to the risk of developing ulcers in the oropharyngeal mucosa.

Children

The use of this medicinal product in children under 18 years of age has not been studied.

Overdose

There is no specific information on the treatment of overdose with this medicinal product. Symptoms. Based on available data for bisphosphonates, adverse reactions in the upper gastrointestinal tract (such as gastrointestinal disturbances, dyspepsia, esophagitis, gastritis, ulceration) or hypocalcemia may occur.

Treatment. To bind the medicinal product, milk or antacids should be administered. Any adverse reactions should be treated symptomatically. Due to the risk of esophageal irritation, vomiting should not be induced. Patients should remain in an upright position.

Side effects.

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 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 and did not require medical intervention (see "Description of individual adverse reactions").

Below is the complete list of known adverse reactions.

The safety of ibandronic acid 2.5 mg once daily orally has been 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 a two-year study in postmenopausal women with osteoporosis (VM16549), the overall safety profile was similar for the 150 mg once-monthly formulation and daily oral ibandronic acid 2.5 mg. The total number of patients who experienced adverse reactions, i.e., adverse events possibly or probably related to the investigational drug, was 22.7% and 25% with the 150 mg once-monthly formulation after 1 and 2 years of treatment, respectively. Most adverse reactions did not lead to discontinuation of treatment. 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 very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10,000, <1/1000), very rare (<1/10,000), and not known (cannot be estimated from available data). Within each frequency category, adverse reactions are listed in order of decreasing severity.

Adverse reactions reported during Phase III studies VM16549 and MF4411 in postmenopausal women receiving ibandronic acid 150 mg once monthly or ibandronic acid 2.5 mg orally daily, and during post-marketing use of ibandronic acid:

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; uncommon – dizziness.

Eye disorders: rare – eye inflammation*†.

Gastrointestinal disorders: common – oesophagitis, gastritis, gastro-oesophageal reflux disease, dyspepsia, diarrhoea, abdominal pain, nausea; uncommon – oesophagitis, including oesophageal ulceration or strictures and dysphagia, vomiting, flatulence; rare – duodenitis.

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

Musculoskeletal and connective tissue disorders: common – arthralgia, myalgia, musculoskeletal pain, muscle cramps, musculoskeletal stiffness; uncommon – back pain; rare – atypical subtrochanteric and diaphyseal femoral fractures†; very rare – osteonecrosis of the jaw*†.

Osteonecrosis of the external auditory canal (an adverse reaction typical of the bisphosphonate class)†; frequency not known – atypical fractures of long bones other than femur.

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

*see information below.

†identified during post-marketing use of ibandronic acid.

Description of individual adverse reactions.

Gastrointestinal adverse reactions.

Patients with a history of gastrointestinal disorders, including those with peptic ulcer without recent bleeding or hospitalization, and patients with dyspepsia or reflux controlled with medication, were included in the once-monthly treatment studies. In these patients, there was no difference in the frequency of upper gastrointestinal adverse events between the 150 mg once-monthly dose and the 2.5 mg daily dose.

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

Anaphylactic reaction/shock.

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

Reporting of suspected adverse reactions.

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

Shelf life.

5 years.

Storage conditions.

No special storage conditions required. Keep out of reach of children.

Packaging.

Film-coated tablets, 150 mg. 1 tablet in a blister; 1 blister in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

FARMATEN S.A.

Manufacturer's address and location of its business operations.

Derwenakion 6, Pallini Attica, 15351, Greece