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Product Name VIVANAT ROMPHARM 1 mg/ml solution for injection in pre-filled syringe International Nonproprietary Name Ibandronic acid Pharmaceutical form Solution for injection. Clear, colorless solution. Composition Each pre-filled syringe contains: Active substance: 3 mg Ibandronic acid (as sodium ibandronate). Excipients: Sodium chloride, glacial acetic acid, sodium acetate trihydrate, 1% acetic acid for pH adjustment, water for injections. The concentration of Ibandronic acid in the solution for injection is 1 mg per ml. Pharmaceutical group and ATC code: Pharmacotherapeutic group: Drugs for bone diseases, Bisphosphonates, ATC code: M05BA06 Pharmacological properties Pharmacodynamic properties Mechanism of action Ibandronic acid is a highly potent bisphosphonate belonging to the group of nitrogen-containing bisphosphonates that selectively act on bone tissue and specifically inhibit osteoclast activity, without directly affecting bone formation. It does not inhibit osteoclast recruitment. Ibandronic acid leads to a progressive increase in bone mass and a reduction in fracture incidence by reducing bone turnover to premenopausal levels in postmenopausal women. Pharmacodynamic effects The pharmacodynamic action of ibandronic acid is the suppression of bone resorption. In vivo, ibandronic acid inhibits bone destruction experimentally induced by cessation of gonadal function, retinoids, tumors, or tumor extracts. In young (rapidly growing) rats, endogenous bone resorption is also inhibited, leading to increased normal bone mass compared to untreated animals. Animal models confirm that ibandronic acid is a potent inhibitor of osteoclastic activity. In growing rats, no evidence of mineralization disorder was observed when doses up to 5000 times the dose required for osteoporosis treatment were administered. Both daily and intermittent (with prolonged intervals without dosing) long-term administration in rats, dogs, and monkeys was associated with the formation of new bone of normal quality and maintenance or increase of mechanical strength, even in the toxic range. In humans, the efficacy of both daily and intermittent administration of ibandronic acid at intervals of 9-10 weeks has been confirmed in a clinical study (MF 4411), in which ibandronic acid showed anti-fracture efficacy. In animal models, ibandronic acid produced biochemical changes indicating dose-dependent inhibition of bone resorption, including degradation of biochemical markers of bone collagen degradation (such as deoxypyridinoline and cross-linked N-telopeptides of type I collagen (NTX)) in urine. Both daily and intermittent (with doses every 9-10 weeks) oral doses, as well as intravenous doses of ibandronic acid in postmenopausal women, caused biochemical changes indicating dose-dependent inhibition of bone resorption. Intravenous injection of ibandronate reduces serum levels of type I collagen (CTX) alpha chain C-telopeptide within 3-7 days of initiating treatment and reduces osteocalcin levels for 3 months. After discontinuation of treatment, there is a return to pathological levels of increased bone resorption prior to treatment, associated with postmenopausal osteoporosis. Histological analysis of bone biopsies after two and three years of treatment with oral doses of ibandronic acid 2.5 mg daily and intermittent intravenous doses of up to 1 mg every 3 months in postmenopausal women showed bone of normal quality and no evidence of mineralization defects. The expected reduction in bone turnover, normal bone quality, and absence of mineralization defects were also observed after two years of treatment with 3 mg VIVANAT ROMPHARM injection. Clinical efficacy Independent risk factors, such as low BMD, age, presence of previous fractures, family history of fractures, high bone turnover, and low body mass index, should be considered when identifying women at increased risk of osteoporotic fractures. Ibandronate 3 mg solution for injection every 3 months Bone mineral density (BMD) Intravenous administration of 3 mg ibandronate every 3 months showed at least equivalent efficacy to oral ibandronic acid 2.5 mg daily in a 2-year, randomized, double-blind, multicenter, non-inferiority study (BM16550) in postmenopausal women (1386 women aged 55-80 years) with osteoporosis (lumbar spine BMD T-score of -2.5 SD at baseline). This was demonstrated both in the primary analysis at one year and in the confirmatory analysis at the two-year endpoint (Table 2). The primary analysis of the BM16550 study data after one year and the confirmatory analysis after 2 years showed non-inferior efficacy of the dosing regimen of 3 mg injection every 3 months compared to the oral dosing regimen of 2.5 mg daily, in terms of mean increase in BMD of the lumbar spine, total hip, femoral neck, and trochanter (Table 2). Table 2: Mean relative change in BMD of the lumbar spine, total hip, femoral neck, and trochanter from baseline after one year of treatment (primary analysis) and after two years (per-protocol population) in study BM 16550. One-year data in study BM 16550 Two-year data in study BM 16550 Mean relative changes from baseline % [95% CI] Ibandronic acid 2.5 mg daily (N=377) VIVANAT ROMPHARM 3 mg injection every 3 months (N=365) Ibandronic acid 2.5 mg daily (N=334) VIVANAT ROMPHARM 3 mg injection every 3 months (N=334) Lumbar spine L2-L4 BMD 3.8 [3.4, 4.2] 4.8 [4.5, 5.2] 4.8 [4.3, 5.4] 6.3 [5.7, 6.8] Total hip BMD 1.8 [1.5, 2.1] 2.4 [2.0, 2.7] 2.2 [1.8, 2.6] 3.1 [2.6, 3.6] Femoral neck BMD 1.6 [1.2, 2.0] 2.3 [1.9, 2.7] 2.2 [1.8, 2.7] 2.8 [2.3, 3.3] Trochanter BMD 3.0 [2.6, 3.4] 3.8 [3.2, 4.4] 3.5 [3.0, 4.0] 4.9 [4.1, 5.7] Furthermore, it was confirmed that injectable ibandronate 3 mg every 3 months prospectively exceeded oral ibandronic acid 2.5 mg daily in terms of lumbar spine BMD increase in a prospectively planned analysis at one year, p<0.001, and at two years, p<0.001. Regarding lumbar spine BMD, in 92.1% of patients receiving 3 mg injection every 3 months, BMD was increased or maintained after 1 year of treatment (i.e., they were responders) compared to 84.9% of patients receiving 2.5 mg orally daily (p=0.002). After 2 years of treatment, in 92.8% of patients receiving 3 mg injections and 84.7% of patients receiving 2.5 mg oral therapy, an increase or maintenance of lumbar spine BMD was observed (p=0.001). Regarding total hip BMD, 82.3% of patients receiving 3 mg injection every 3 months were classified as responders after one year, compared to 75.1% of patients receiving 2.5 mg orally daily (p=0.02). After 2 years of treatment, in 85.6% of patients receiving 3 mg injections and 77.0% of patients receiving 2.5 mg oral therapy, total hip BMD was increased or maintained (p=0.004). The proportion of patients with increased or maintained BMD in both the lumbar spine and total hip area after one year was 76.2% in the group receiving 3 mg injection every 3 months and 67.2% in the group receiving 2.5 mg orally daily (p=0.007). After two years, 80.1% and 68.8% of patients met this criterion in the group receiving 3 mg injection every 3 months and the group receiving 2.5 mg daily orally, respectively (p=0.001). Biochemical markers of bone turnover A clinically significant reduction in serum CTX levels was observed at all measured time points. At 12 months, median relative changes from baseline were -58.6% for the 3 mg intravenous injection regimen every 3 months and -62.6% for the 2.5 mg oral daily regimen. Furthermore, 64.8% of patients receiving the 3 mg injection every 3 months were identified as responders (defined as ≥50% reduction from baseline), compared to 64.9% of patients receiving 2.5 mg orally daily. The reduction in serum CTX was maintained for 2 years, with more than half of patients identified as responders in both treatment groups. Based on the results of the BM 16550 study, intravenous injection of ibandronate 3 mg every 3 months is expected to be at least as effective in preventing fractures as the oral ibandronic acid regimen of 2.5 mg daily. Ibandronic acid 2.5 mg daily tablets In the initial three-year, randomized, double-blind, placebo-controlled fracture study (MF 4411), a statistically significant and clinically relevant reduction in the incidence of new radiographic morphometric and clinical vertebral fractures was demonstrated (Table 3). In this study, ibandronic acid was evaluated when administered orally at doses of 2.5 mg daily and 20 mg intermittently. Ibandronic acid was administered 60 minutes before the first intake of food or drink of the day (post-dose fasting period). The study included women aged 55 to 80 years, who were at least 5 years postmenopausal, with a lumbar spine BMD of -2 to -5 SD below the premenopausal mean (T-score) in at least one vertebra [L1-L4] and who had one to four prevalent vertebral fractures. All patients received 500 mg calcium and 400 IU vitamin D daily. Efficacy was assessed in 2928 patients. Ibandronic acid 2.5 mg daily administration showed a statistically significant and clinically relevant reduction in the incidence of new vertebral fractures. This regimen reduced the incidence of new radiographic vertebral fractures by 62% (p=0.0001) over the three years of the study. After 2 years, a relative risk reduction of 61% (p=0.0006) was observed. A statistically significant difference (p=0.056) was not achieved after 1 year of treatment. The anti-fracture effect was sustained throughout the duration of the study. No signs of reduced efficacy over time were observed. The incidence of clinical vertebral fractures was also significantly reduced by 49% after 3 years (p=0.011). The strong effect on vertebral fractures was also reflected in a statistically significant reduction in the rate of height loss compared to placebo (p<0.0001). Table 3: Results of the 3-year fracture study MF 4411 (%, 95 % CI) Placebo (N=974) Ibandronic acid 2.5 mg daily (N=977) Relative risk reduction of new morphometric vertebral fractures 62% (40.9, 75.1) Incidence of new morphometric vertebral fractures 9.56% (7.5, 11.7) 4.68% (3.2, 6.2) Relative risk reduction of clinical vertebral fractures 49% (14.03, 69.49) Incidence of clinical vertebral fractures 5.33% (3.73, 6.92) 2.75% (1.61, 3.89) Mean change in BMD of the lumbar spine from baseline at year 3 1.26% (0.8, 1.7) 6.54% (6.1, 7.0) Mean change in BMD of the total hip from baseline at year 3 -0.69% (-1.0, -0.4) 3.36% (3.0, 3.7) The therapeutic effect of ibandronic acid was further assessed in a subpopulation analysis of patients with a baseline lumbar spine BMD T-score below 2.5 (Table 4). The reduction in vertebral fracture risk was significantly consistent with the rates observed in the overall population. Table 4: Results of the 3-year fracture study MF 4411 (%, 95 % CI) for patients with a baseline lumbar spine BMD T-score below -2.5. Placebo (N=587) Ibandronic acid 2.5 mg daily (N=575) Relative risk reduction of new morphometric vertebral fractures 59% (34.5, 74.3) Incidence of new morphometric vertebral fractures 12.54% (9.53, 15.55) 5.36% (3.31, 7.41) Relative risk reduction of clinical vertebral fractures 50% (9.49, 71.91) Incidence of clinical vertebral fractures 6.97% (4.67, 9.27) 3.57% (1.89, 5.24) Mean change in BMD of the lumbar spine from baseline at year 3 1.13% (0.6, 1.7) 7.01% (6.5, 7.6) Mean change in BMD of the total hip from baseline at year 3 -0.70% (-1.1, -0.2) 3.59% (3.1, 4.1) In the overall population of patients in the MF4411 study, no reduction in non-vertebral fractures was observed, however, ibandronic acid was effective in the high-risk subpopulation (femoral neck BMD T-score < -3.0) with daily administration, where a 69% reduction in the risk of non-vertebral fractures was observed. Daily oral treatment with ibandronic acid 2.5 mg tablets led to a progressive increase in BMD in both vertebral and non-vertebral skeletal areas. The three-year increase in lumbar spine BMD compared to placebo was 5.3% and 6.5% from baseline. The increase in the hip area compared to baseline was 2.8% in the femoral neck area, 3.4% in the total hip area, and 5.5% at the trochanter. Biochemical markers of bone turnover (such as urinary CTX and serum osteocalcin) showed the expected pattern of suppression to premenopausal levels and reached maximum suppression within 3-6 months of daily use of 2.5 mg ibandronic acid. A clinically significant reduction in biochemical markers of bone resorption by 50% was observed one month after initiating treatment with ibandronic acid 2.5 mg. Pediatric population (see section "Dosage and administration" and section "Pharmacokinetic properties"). VIVANAT ROMPHARM has not been studied in the pediatric population, therefore efficacy or safety data are not available for this patient population. Pharmacokinetic properties The primary pharmacological action of ibandronic acid on bone is not directly related to actual plasma concentrations, as shown by various studies in animals and humans. Plasma concentration of ibandronic acid increases proportionally to the dose from 0.5 mg to 6 mg after intravenous administration. Absorption is not applicable. Distribution After initial systemic exposure, ibandronic acid rapidly binds to bone or is excreted in urine. In humans, the apparent volume of distribution is at least 90 L, and the amount of dose reaching bone is estimated to be 40-50% of the circulating dose. Protein binding in human plasma is approximately 85% - 87% (determined in vitro at therapeutic concentrations of ibandronic acid) and therefore the potential for drug interactions due to displacement is low. Biotransformation There is no evidence that ibandronic acid is metabolized in animals or humans. Elimination Ibandronic acid is eliminated from the circulation by absorption into bone (estimated to be 40-50% in postmenopausal women) and the remaining portion is excreted unchanged by the kidneys. Observed apparent half-life ranges widely, with apparent terminal half-life primarily between 10-72 hours. Since calculated values largely depend on the duration of the study, dose used, and sensitivity of the assay, the true terminal half-life is likely to be considerably longer, as is generally the case for other bisphosphonates. Early plasma levels fall rapidly, reaching 10% of peak values within 3 and 8 hours of intravenous or oral administration, respectively. The total clearance of ibandronic acid is low, with mean values in the range of 84 - 160 ml/min. Renal clearance (approximately 60 ml/min in healthy postmenopausal women) accounts for 50-60% of total clearance and is related to creatinine clearance. The difference between apparent total and renal clearance is thought to reflect bone uptake. The secretory pathway does not appear to involve known acidic or basic transport systems involved in the excretion of other active substances (see section "Interactions with other medicinal products and other forms of interaction"). Furthermore, ibandronic acid does not inhibit major human liver P450 isoenzymes and does not induce the hepatic cytochrome P450 system in rats. Pharmacokinetics in special clinical situations Sex The pharmacokinetics of ibandronic acid are similar in men and women. Race There is no evidence of any clinically significant interethnic differences between Mongoloid and Caucasian races in the distribution of ibandronic acid. Available data on patients of Negroid origin are limited. Patients with renal impairment Renal clearance of ibandronic acid in patients with varying degrees of renal impairment is linearly related to creatinine clearance (CLcr). Dose adjustment is not required for patients with mild or moderate renal impairment (CLcr ≥ 30 ml/min). Subjects with severe renal impairment (CLcr < 30 ml/min) who received 10 mg of ibandronic acid orally daily for 21 days had 2-3 times higher plasma concentrations than subjects with normal renal function, and total clearance of ibandronic acid was 44 ml/min. After intravenous administration of 0.5 mg of ibandronic acid, total, renal, and non-renal clearance were reduced by 67%, 77%, and 50%, respectively, in subjects with severe renal impairment, but no reduction in tolerance associated with increased exposure was observed. Due to limited clinical experience, VIVANAT ROMPHARM is not recommended in patients with severe renal impairment (see section "Dosage and administration" and section "Special warnings and precautions for use"). The pharmacokinetics of ibandronic acid in patients with end-stage renal disease have only been evaluated in a small number of patients managed by hemodialysis; therefore, the pharmacokinetics of ibandronic acid in patients not on hemodialysis are unknown. Due to limited available 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 pharmacokinetic data for 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 by bone uptake. Therefore, dose adjustment is not required in patients with hepatic impairment. Elderly population (see section "Dosage and administration") In a multivariate analysis, age was not found to be an independent factor for any of the pharmacokinetic parameters studied. Since renal function decreases with age, renal function is the only factor to consider (see section on impaired renal function). Pediatric population (see section "Dosage and administration" and section "Pharmacodynamic properties") There is no data on the use of ibandronate in this age group. Therapeutic indications Treatment of osteoporosis in postmenopausal women at increased risk of fracture (see section "Pharmacodynamic properties"). Reduction in the risk of vertebral fractures has been demonstrated; efficacy on hip fractures has not been established. Dosage and administration Patients being treated with VIVANAT ROMPHARM should be given the package leaflet and patient reminder card. Dosage The recommended dose of ibandronic acid is 3 mg, administered as an intravenous injection over 15-30 seconds, every three months. Patients should also receive calcium and vitamin D supplementation (see section "Special warnings and precautions for use" and section "Interactions with other medicinal products and other forms of interaction"). If a dose is missed, the injection should be administered as soon as possible. Thereafter, injections should be scheduled every 3 months from the date of the last injection. The optimal duration of bisphosphonate treatment for osteoporosis has not been established. The need for continued treatment should be reassessed periodically based on the benefit and potential risks of VIVANAT ROMPHARM for the individual patient, especially after 5 or more years of use. Special populations Patients with renal impairment The use of VIVANAT ROMPHARM injection is not recommended in patients with serum creatinine levels above 200 µmol/l (2.3 mg/dl) or creatinine clearance (measured or estimated) below 30 ml/min, due to limited clinical data obtained from studies involving such patients (see section "Special warnings and precautions for use" and section "Pharmacokinetic properties"). Dose adjustment is not required for patients with mild or moderate renal impairment with serum creatinine ≤ 200 µmol/l (2.3 mg/dl) or creatinine clearance (measured or estimated) ≥ 30 ml/min. Patients with hepatic impairment Dose adjustment is not required (see section "Pharmacokinetic properties"). Elderly population (>65 years) Dose adjustment is not required (see section "Pharmacokinetic properties"). Pediatric population There is no relevant use data for VIVANAT ROMPHARM in children under 18 years of age, and it has not been studied in this population (see section "Pharmacodynamic properties" and "Pharmacokinetic properties"). Method of administration For intravenous use over 15-30 seconds, every three months. The intravenous administration route must be strictly followed (see section "Special warnings and precautions for use"). Contraindications - Hypersensitivity to ibandronic acid or to any of the excipients listed in the "Composition" section. - Hypocalcemia Adverse effects Summary of the safety profile The most serious reported adverse reactions are anaphylactic reaction/shock, atypical femoral fractures, osteonecrosis of the jaw, and ocular inflammation (see paragraph "Description of selected adverse reactions" and section "Special warnings and precautions for use"). The most frequently reported adverse reactions are arthralgia and influenza-like symptoms. These symptoms are usually associated with the first dose administration, are of short duration, mild to moderate in intensity, and usually resolve with continued treatment without the need for therapeutic measures (see paragraph "Influenza-like illness"). List of adverse reactions in tabular form Table 1 presents a complete list of known adverse reactions. The safety of oral treatment with ibandronic acid 2.5 mg daily was evaluated in 1251 patients treated in 4 placebo-controlled clinical studies, with the vast majority of patients participating in the main three-year fracture study (MF 4411). In the main two-year study in postmenopausal women with osteoporosis (BM16550), the safety of intravenous injection of VIVANAT ROMPHARM 3 mg every 3 months and oral administration of ibandronic acid 2.5 mg daily was generally similar. The overall proportion of patients who developed an adverse reaction was 26.0% and 28.6% for VIVANAT ROMPHARM 3 mg injection every 3 months after one year and two years, respectively. The majority of adverse reactions did not lead to discontinuation of therapy. Adverse reactions are listed by MedDRA system organ class and frequency category. Frequency categories are defined using the following convention: 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), unknown (cannot be estimated from available data). Within each frequency group, adverse reactions are presented in order of decreasing severity. Table 1: Adverse reactions that occurred in postmenopausal women receiving VIVANAT ROMPHARM 3 mg injection every 3 months or ibandronic acid 2.5 mg daily in Phase III studies BM16550 and MF 4411, and in post-marketing experience. System organ class Common Uncommon Rare Very rare Immune system disorders Asthma exacerbation Hypersensitivity reaction Anaphylactic reaction/shock*† Metabolism and nutrition disorders Hypocalcemia† Nervous system disorders Headache Eye disorders Ocular inflammatory diseases*† Vascular disorders Phlebitis/thrombophlebitis Gastrointestinal disorders Gastritis, dyspepsia, diarrhea, abdominal pain, nausea, constipation Skin and subcutaneous tissue disorders Stevens-Johnson syndrome†, erythema multiforme†, bullous dermatitis† Rash Angioneurotic edema, facial swelling/edema, urticaria Stevens-Johnson syndrome†, erythema multiforme†, bullous dermatitis† Musculoskeletal and connective tissue disorders Arthralgia, myalgia, musculoskeletal pain, back pain Bone pain Atypical subtrochanteric and diaphyseal fractures of the femur* Osteonecrosis of the jaw*† Osteonecrosis of the external auditory canal (class side effect of bisphosphonates)† General disorders and administration site conditions Influenza-like illness*, fatigue Reactions at the injection site, asthenia * Further information see below † Identified in post-marketing experience. Description of selected adverse reactions Influenza-like illness Influenza-like illness includes events reported as acute phase reaction 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, predominantly in cancer patients treated with bone resorption inhibiting drugs such as ibandronic acid (see section "Special warnings and precautions for use"). Cases of osteonecrosis of the jaw have been reported with the use of ibandronic acid in the post-marketing period. Ocular inflammatory diseases Ocular inflammatory events such as uveitis, episcleritis, and scleritis have been reported with the use of ibandronic acid. In some cases, these events did not resolve until ibandronic acid was discontinued. Anaphylactic reaction/shock Cases of anaphylactic reaction/shock, including fatal events, have been reported in patients treated with intravenously administered ibandronic acid. Reporting of suspected adverse reactions Reporting of suspected adverse reactions is important after the medicinal product is authorized. It allows for continuous monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions through the national reporting system. Special warnings and precautions for use Failure of administration Care must be taken to avoid intra-arterial or paravenous administration of VIVANAT ROMPHARM injection, as this may cause tissue damage. Hypocalcemia VIVANAT ROMPHARM, like other intravenously administered bisphosphonates, may cause a transient decrease in serum calcium levels. Existing hypocalcemia must be corrected before initiating VIVANAT ROMPHARM injection therapy. Other disorders of bone and mineral metabolism must also be effectively treated before initiating therapy with injectable VIVANAT ROMPHARM. All patients should receive adequate calcium and vitamin D supplementation. Anaphylactic reaction/shock Cases of anaphylactic reaction/shock, including fatal events, have been reported in patients treated with intravenously administered ibandronic acid. Appropriate medical assistance and monitoring measures should be available when administering VIVANAT ROMPHARM intravenous injection. In the event of anaphylactic or other severe hypersensitivity/allergic reactions, discontinue the injection immediately and initiate appropriate treatment. Renal impairment Patients with concomitant diseases or those using medicinal products with potential for adverse effects on the kidneys should be regularly monitored during treatment in accordance with appropriate medical practice. Due to limited clinical experience, injectable VIVANAT ROMPHARM is not recommended for patients with serum creatinine levels exceeding 200 µmol/l (2.3 mg/dl) or creatinine clearance less than 30 ml/min (see section "Dosage and administration" and section "Pharmacokinetic properties"). Patients with heart failure In patients at risk of heart failure, hyperhydration should be avoided. Osteonecrosis of the jaw Osteonecrosis of the jaw (ONJ) has been very rarely reported in the post-marketing period in patients receiving ibandronate for osteoporosis (see section "Adverse effects"). Initiation of treatment or a new course of treatment in patients with unhealed open lesions of the oral mucosa should be postponed. A dental examination with prophylactic dental procedures is recommended before starting treatment with VIVANAT ROMPHARM, and an individual benefit-risk assessment should be performed in patients with concomitant risk factors. When assessing the risk of developing osteonecrosis of the jaw in a patient, the following risk factors should be considered: - The potential of the medicinal product to suppress bone resorption (higher risk for highly potent compounds), route of administration (higher risk with parenteral use), and cumulative dose of bone resorption therapy - Cancer, concomitant diseases (e.g., anemia, coagulopathies, infection), smoking - Concomitant therapy: corticosteroids, chemotherapy, angiogenesis inhibitors, radiotherapy of the head and neck - Poor oral hygiene, periodontal disease, poorly fitting prosthesis, history of dental disease, invasive dental procedures, e.g., tooth extraction. All patients should be informed about the need for proper oral hygiene, routine dental check-ups, and immediate reporting of any oral symptoms such as loose teeth, pain or swelling, or unhealed ulcers or discharge during treatment with VIVANAT ROMPHARM. Invasive dental procedures during treatment should only be performed after careful consideration and should be avoided in close proximity to VIVANAT ROMPHARM administration. A management plan for patients with osteonecrosis of the jaw should be established in collaboration between the treating physician and a dentist or maxillofacial surgeon experienced in the treatment of osteonecrosis of the jaw. Consideration should be given to temporarily discontinuing treatment with VIVANAT ROMPHARM until the condition improves and, as far as possible, predisposing risk factors are mitigated. Osteonecrosis of the external auditory canal Osteonecrosis of the external auditory canal has been reported with bisphosphonate use, predominantly associated with long-term therapy. Possible risk factors for osteonecrosis of the external auditory canal include steroid use and chemotherapy and/or local risk factors such as infection or trauma. The possibility of developing osteonecrosis of the external auditory canal should be considered in patients receiving bisphosphonates who experience ear symptoms, including chronic ear infections. Atypical fractures of the femur Atypical subtrochanteric and diaphyseal fractures of the femur have been reported during bisphosphonate therapy, mainly in patients receiving long-term treatment for osteoporosis. These transverse or short oblique fractures can occur anywhere along the femur, from below the lesser trochanter to the supracondylar flare. These fractures occur after minimal trauma or without trauma, and some patients experience pain in the hip or groin area, often associated with imaging features of stress fractures, weeks or months before the development of a complete femoral fracture. Fractures are often bilateral; therefore, in patients treated with bisphosphonates who have sustained a femoral neck fracture, the contralateral femur should be examined. Impaired healing of these fractures has also been reported. In patients with an atypical femoral fracture, discontinuation of bisphosphonate therapy should be considered while awaiting assessment of the patient's condition, based on an individual benefit-risk assessment. Patients should be advised during bisphosphonate treatment to report any pain in the thigh, hip joint, or groin area, and any patient with such symptoms should be evaluated to rule out an incomplete femoral fracture. VIVANAT ROMPHARM is virtually sodium-free. Effect on ability to drive and use machines Based on the pharmacodynamic and pharmacokinetic profile and reported adverse reactions, VIVANAT ROMPHARM is expected to have no or negligible influence on the ability to drive and use machines. Fertility, pregnancy and lactation Pregnancy VIVANAT ROMPHARM is intended for use only in postmenopausal women and should not be taken by women of childbearing potential. There are no adequate data on the use of ibandronic acid in pregnant women. Studies in rats have shown some reproductive toxicity. The potential risk to humans is unknown. VIVANAT ROMPHARM should not be used during pregnancy. Breastfeeding It is unknown whether ibandronic acid is excreted in human milk. Studies in lactating rats have shown low levels of ibandronic acid in milk after intravenous administration. VIVANAT ROMPHARM should not be used during breastfeeding. Fertility There is no data on the effect of ibandronic acid in humans. In reproductive studies in rats, ibandronic acid reduced fertility when administered orally. In studies in rats using the intravenous route of administration, ibandronic acid reduced fertility at high daily doses. Interactions with other medicinal products and other forms of interaction Metabolic interactions are unlikely, as ibandronic acid does not inhibit major human liver P450 isoenzymes and has been shown not to induce the hepatic cytochrome P450 system in rats (see section "Pharmacokinetic properties"). Ibandronic acid is eliminated solely by renal excretion and does not undergo biotransformation. Overdose There is no specific information on the treatment of overdose with ibandronic acid. Based on knowledge of compounds in this class, intravenous overdose may cause hypocalcemia, hypophosphatemia, and hypomagnesemia. Clinically significant reductions in serum calcium, phosphorus, and magnesium levels should be corrected by intravenous administration of calcium gluconate, potassium or sodium phosphate, and magnesium sulfate, respectively. Special precautions for disposal and other handling When the medicinal product is administered into an existing system intended for intravenous infusion, the infusate should be limited to isotonic saline or 50 mg/ml (5%) glucose solution. This also applies to solutions used to flush butterfly and other devices. Any unused solution for injection, syringe, and injection needle must be disposed of in accordance with local requirements. The release of pharmaceuticals into the environment should be minimized. The following points must be strictly adhered to regarding the use and disposal of syringes and other medicinal products: • Needles and syringes must not be reused. • Place all used needles and syringes in a sharps container (puncture-resistant disposable container). • Keep this container out of reach of children. • Used sharps containers should not be placed in household waste. • Dispose of the full container in accordance with local requirements or as instructed by your healthcare professional. Incompatibility VIVANAT ROMPHARM solution for injection must not be mixed with calcium-containing solutions or other intravenously administered medicinal products. Type and content of container Pre-filled syringes (5 ml) made of Type I colorless glass, containing 3 ml of solution for injection, equipped with a plunger stopper, plunger rod, and backstop. Packs of 1 pre-filled syringe and 1 injection needle or 4 pre-filled syringes and 4 injection needles. Special precautions for storage Store below 25°C, in the original packaging. Shelf life 2 years Legal status Prescription-only medicine, group II, dispensed with prescription form №3. See also: Bonviva - Bonviva 150mg 3 tablets