Instructions for use BONVIVA tablets

Composition and release form

14 pcs in blister; There are 2 blisters in a cardboard pack.

in a blister 1 or 3 pcs; 1 blister in a cardboard pack.

in a syringe tube 3 ml (complete with a sterile needle); 1 set in a cardboard pack.

Pharmacodynamics

Ibandronic acid is a highly active nitrogen-containing bisphosphonate, an inhibitor of bone resorption and osteoclast activity. Ibandronic acid prevents bone destruction caused by gonadal blockade, retinoids, tumors and tumor extracts in vivo. Inhibits endogenous resorption in young (fast-growing) rats, which is manifested by higher bone mass compared to intact animals.

Does not interfere with bone mineralization when administered in doses more than 5000 times higher than doses for the treatment of osteoporosis and does not affect the process of replenishment of the osteoclast pool. The selective effect of ibandronic acid on bone tissue is due to its high affinity for hydroxyapatite, which constitutes the mineral matrix of bone.

Ibandronic acid inhibits bone resorption in a dose-dependent manner and does not have a direct effect on bone formation. In menopausal women, it reduces the increased rate of bone tissue turnover to the level of reproductive age, which leads to a general progressive increase in bone mass, a decrease in the breakdown of bone collagen (concentrations of deoxypyridinoline and cross-linked C- and N-telopeptides of type I collagen) in urine and blood serum , incidence of fractures and increased BMD.

High activity and therapeutic range provide the possibility of a flexible dosage regimen and intermittent administration of the drug with a long period without treatment in relatively low doses.

Efficiency

Film-coated tablets, 2.5 mg. Both continuous and intermittent (one 9-10 week break per quarter) long-term oral use of Bonviva® in the form of 2.5 mg film-coated tablets in menopausal women is accompanied by dose-dependent inhibition of bone resorption, incl. a decrease in the breakdown of bone collagen (the concentration of deoxypyridinoline and cross-linked C- and N-telopeptides of type I collagen) in urine and blood serum, an increase in BMD and a decrease in the incidence of fractures.

After cessation of treatment, there is a return to the pre-treatment increased rate of bone resorption in postmenopausal osteoporosis.

Histological analysis of bone tissue samples obtained after 2 and 3 years of treatment in menopausal women showed normal bone tissue characteristics and no signs of mineralization disorders.

Daily administration of Bonviva® in the form of film-coated tablets, 2.5 mg for 3 years (randomized, double-blind, placebo-controlled study MF4411) is accompanied by a statistically significant reduction in the incidence of radiographic and morphometrically confirmed vertebral fractures by 62%, and clinically confirmed vertebral body fractures by 49%. The reduction in bone loss was accompanied by a significantly less pronounced decrease in the height of patients compared to placebo.

Prevention of fractures was maintained throughout the study, and there was no evidence of the effect fading over time.

A similar reduction in the relative risk of non-vertebral fractures was revealed by 69% in patients from the high-risk group (BMD T coefficient for the femoral neck less than -3.0 SD). These data are consistent with the results of clinical studies of other bisphosphonates.

With daily use of Bonviva® for 3 years, the BMD of the lumbar vertebrae increases by 6.5% compared to the baseline.

Film-coated tablets, 150 mg each, and solution for intravenous administration. Bone Mineral Density (BMD)

Taking Bonviva® 150 mg once a month for a year increases the average BMD of the lumbar vertebrae, hip, femoral neck and trochanter by 4.9, 3.1, 2.2 and 4.6%; IV administration of Bonviva® 3 mg once every 3 months for 1 year increases the average BMD of the femur, femoral neck and trochanter by 2.4, 2.3 and 3.8%, respectively.

Regardless of the duration of menopause and the degree of initial bone loss, the use of Bonviva® leads to a significantly more pronounced change in BMD than placebo. The effect of treatment within a year, defined as an increase in BMD, is observed in 83.9% (when taking film-coated tablets) and 92.1% (when administered intravenously) of patients.

Biochemical markers of bone resorption

Film-coated tablets, 2.5 mg. Biochemical markers of bone resorption (urinary concentrations of type I procollagen C-terminal peptide (CTX) and serum osteocalcin) decline to their levels during reproductive age; the maximum reduction is observed after 3-6 months of treatment. Just one month after starting the use of Bonviva 2.5 mg daily and 20 mg intermittently, a clinically significant reduction in biochemical markers of bone resorption was achieved by 50 and 78%, respectively; Moreover, a slight decrease in these indicators was noted after a week of treatment. A clinically significant decrease in biochemical markers of bone resorption (urinary CTX concentrations) is observed one month after the start of treatment.

Bonviva 2.5 mg daily for the prevention of postmenopausal osteoporosis (study MF4499) increased mean lumbar spine BMD by 1.9% compared with baseline. Regardless of the duration of menopause and the degree of initial loss of basic bone tissue, the use of Bonviva® leads to a significantly more pronounced change in the BMD of the lumbar vertebrae. When using the drug Bonviva®, the treatment effect, defined as an increase in BMD compared to the baseline, is observed in 70% of patients.

Film-coated tablets, 150 mg each, and solution for intravenous administration. A 28% decrease in serum CTX concentration was noted within 24 hours after the first dose of 150 mg Bonviva®, with a maximum decrease of 68% after 6 days. After the third and fourth doses of Bonviva® 150 mg, the maximum decrease in serum CTX by 74% was observed after 6 days. 28 days after taking the fourth dose, a decrease in the suppression of biochemical markers of bone resorption was noted to 56%.

A clinically significant decrease in serum CTX was obtained after 3, 6 and 12 months of therapy. After a year of therapy with Bonviva® 150 mg, the reduction was 76%; compared with the initial value, when using 3 mg IV - 58.6%.

A decrease in CTX of more than 50% compared to the initial value was observed in 83.5% of patients receiving Bonviva® 150 mg once every 28 days.

Instructions for use BONVIVA tablets

Mechanism of action

Ibandronic acid is a potent bisphosphonate belonging to the group of nitrogen-containing bisphosphonates that acts selectively on bone tissue and specifically inhibits osteoclast activity without directly affecting bone formation. This does not disrupt the replenishment of the osteoclast pool. Ibandronic acid results in a progressive increase in bone mass and a reduction in fracture rates by reducing increased bone turnover in postmenopausal women to levels seen in premenopausal women.

Pharmacodynamic effects

The pharmacodynamic effect of ibandronic acid is the inhibition of bone resorption. In vivo, ibandronic acid prevents experimentally induced bone destruction that is caused by gonadal suppression, retinoids, tumors and tumor extracts. In young (rapidly growing) rats, endogenous bone resorption is also inhibited, resulting in increased bone mass compared to untreated animals.

Ibandronic acid has been shown to be a potent inhibitor of osteoclast activity in animal models. In growing rats, there was no evidence of impairment of mineralization even at doses 5,000 times the dose required to treat osteoporosis.

Both daily and intermittent (long drug-free intervals) long-term administration of the drug to rats, dogs and monkeys was associated with the formation of new structured bone mass and preserved or improved mechanical strength, even when doses were used in the toxic range. In humans, the effectiveness of daily and intermittent administration of ibandronic acid over a drug-free interval of 9-10 weeks was supported by a clinical study (MF4411) in which ibandronic acid demonstrated efficacy in fractures.

In animal models, ibandronic acid caused biochemical changes indicative of dose-dependent inhibition of bone resorption, including a decrease in biochemical markers of bone collagen breakdown in urine (such as deoxypyridinoline and cross-linked N-telopeptides of type I collagen (NTX)).

In a phase 1 bioequivalence study of 72 postmenopausal women, subjects received oral Bonviva 150 mg every 28 days (4 doses total). This study found that a decrease in serum cross-linked C-telopeptide type I collagen (CTX) concentrations was observed as early as the first 24 hours after the first dose (an average of 28%), and an average maximum decrease in concentration (of 69%). ) was observed after 6 days. After the 3rd and 4th doses, the mean maximum decrease in concentration 6 days after each dose was 74%, and 28 days after the 4th dose, the average decrease in concentration was 56%. After discontinuation of the drug, the suppression of biochemical markers of bone resorption ceases.

Clinical effectiveness

Independent risk factors, such as low bone mineral density, age, previous fractures, family history of fractures, high bone turnover, and low body mass index, should be used to identify women at increased risk of osteoporotic fractures.

Bonviva® 150 mg once monthly: Bone mineral density (BMD)

Bonviva® 150 mg once monthly was shown to be at least as effective as ibandronic acid 2.5 mg daily in increasing BMD in a 2-year, double-blind, multicenter study (BM 16549) in postmenopausal women with osteoporosis (BMD). lumbar spine:

• this was demonstrated in both the primary analysis at 1 year and the confirmatory analysis at 2 years (Table 2).

Table 2:

• Mean relative deviation from baseline BMD of the lumbar spine, hip, femoral neck, and trochanter at one year (primary analysis) and two years of treatment (per-protocol population) in the BM 16550 study.

In addition, in a prospective analysis, it was proven that Bonviva® at a dosing regimen of 150 mg once a month is superior to Bonviva® 2.5 mg daily in terms of the degree of increase in BMD of the lumbar vertebrae (p = 0.002 in the first year of the study and p = 0.002 in the second year of the study p less than 0.001).

After the first year of the study (primary analysis), 91.3% (p=0.005) of patients receiving Bonviva® 150 mg once monthly, compared with 84.0% of patients receiving Bonviva® 2.5 mg daily, had an increase in lumbar BMD. vertebrae or maintaining its original level. At the end of the second year, 93.5% (p=0.004) of patients receiving Bonviva 150 mg once monthly and 86.4% of patients receiving Bonviva 2.5 mg daily had a positive response to therapy.

Regarding hip BMD values, after the first year of the study, 90.0% (p less than 0.001) of patients receiving Bonviva® 150 mg once a month and 76.7% of patients receiving Bonviva® 2.5 mg daily experienced an increase in BMD or maintaining its original level. By the end of the second year, 93.4% (p less than 0.001) of patients receiving Bonviva 150 mg once monthly and 78.4% of patients receiving Bonviva 2.5 mg daily had an increase in hip BMD or maintained its baseline level.

Using a more stringent criterion that included global assessment of lumbar vertebrae and hip BMD, at the end of the first year of the study, a positive response was observed in 83.9% (p less than 0.001) of patients receiving Bonviva® 150 mg once a month, and in 65.7 % of patients receiving Bonviva® 2.5 mg daily. By the end of the second year, in 87.1% (p less than 0.001) of patients receiving Bonviva 150 mg once a month, and in 70.5% of patients receiving Bonviva 2.5 mg daily.

Biochemical markers of bone remodeling

Clinically significant reductions in serum CTX concentrations were obtained after 3, 6, 12 and 24 months of therapy. After a year of treatment with Bonviva 150 mg once a month (primary analysis), the average reduction was 76%, and when taking the drug at a dose of 2.5 mg daily - 67%. By the end of the second year of the study, the average reduction was 68% when taking Bonviva® 150 mg once a month, and 62% when taking Bonviva® at a dose of 2.5 mg daily.

In a one-year study, 83.5% (p=0.006) of patients receiving Bonviva 150 mg once monthly and 73.9% of patients receiving ibandronic acid 2.5 mg daily were reported as responders (defined as >50% reduction). from the initial level). At the two-year study, 78.7% (p=0.002) and 65.6% of patients were identified as responders at 150 mg monthly and 2.5 mg daily, respectively.

Study BM16549 showed that Bonviva 150 mg once monthly and 2.5 mg daily were at least equivalent in reducing fracture risk.

Ibandronic acid 2.5 mg daily

An initial 3-year, randomized, double-blind, placebo-allocated fracture study (MF4411) demonstrated a statistically significant and medically significant reduction in the incidence of new radiographic morphometric and clinical vertebral fractures (Table 3). This study evaluated oral ibandronic acid 2.5 mg daily and 20 mg intermittently as an investigational regimen. Ibandronic acid was administered 60 minutes before the first meal or drink of the day (post-dose fasting period). The study included women aged between 55 and 80 years with a postmenopausal duration of at least 5 years, whose lumbar spine BMD was -2 to -5 SD below the premenopausal mean (T-score) in at least one vertebra [ L1-L4], and who had one to four major vertebral fractures. All patients received 500 mg calcium and 400 IU vitamin D daily. Efficacy was assessed in 2928 patients. Daily dosing of ibandronic acid 2.5 mg showed a statistically significant and medically significant reduction in the incidence of new vertebral fractures. This regimen reduced the incidence of new radiographic vertebral fractures by 62% (p=0.0001) after 3 years of the study. A relative risk reduction of 61% was observed after 2 years (p=.0006). No statistically significant difference was achieved after 1 year of therapy (p=0.056). Effectiveness in preventing fractures was stable during the study. No decrease in effectiveness was observed over time.

The incidence of clinical vertebral fractures was also significantly reduced by 49% (p=0.011) after three years (p=0.011). The significant effect on vertebral fractures was also confirmed by a statistically significant reduction in height loss compared with placebo (p < 0.0001).

Table 3: Three-year MF4411 fracture study results (%, 95% CI)

The effectiveness of treatment with ibandronic acid was further assessed by analyzing the subpopulation of patients who at baseline had a lumbar BMD T-score below -2.5. The reduction in the risk of vertebral fracture was comparable to the reduction in the overall population.

Table 4: Results from the 3-year MF4411 fracture study (%, 95% CI) for patients with lumbar BMD with a T-score below -2.5 at baseline

There was no significant reduction in the risk of nonvertebral fractures in the entire patient population of the MF4411 study, but in the analysis of a subpopulation of patients at high risk (femoral neck BMD T-score < -3.0), daily ibandronic acid was effective. The risk reduction for nonvertebral fractures in this patient population was 69%.

Daily intake of ibandronic acid at a dose of 2.5 mg leads to a progressive increase in BMD in the vertebral and non-vertebral parts of the skeletal system.

The increase in lumbar BMD in the three-year study compared with placebo was 5.3% and 6.5% when compared with baseline. The increase in femoral BMD compared to baseline was 2.8% for the femoral neck, 3.4% for the total hip, and 5.5%. % for the trochanter of the femur. Biochemical markers of bone turnover (such as urinary CTX and serum osteocalcin) showed expected levels of suppression to premenopausal levels and peaked at 3 to 6 months.

A clinically significant reduction of 50% in biochemical markers of bone resorption was observed one month after initiation of treatment with ibandronic acid 2.5 mg.

Upon cessation of treatment, there is a return to the pathological level of increased pre-treatment bone resorption associated with postmenopausal osteoporosis.

Histological analysis of bone tissue biopsies after two and three years of treatment in postmenopausal women showed normal bone structure and no signs of mineralization defect.

Children

Bonviva has not been studied in children and therefore no efficacy or safety data are available in this patient population.

Preclinical safety data

Toxic effects, such as signs of kidney damage, were observed in dogs only at concentrations well above maximum human doses, indicating little clinical significance.

Mutagenicity/Carcinogenicity:

No indications of carcinogenic potential were received. Genotoxicity tests revealed no evidence of genetic activity for ibandronic acid.

Reproductive toxicity:

There was no evidence of direct fetal toxicity or teratogenicity from oral administration of ibandronic acid in rats and rabbits, and no adverse effects on the development of F1 rat offspring were observed at doses at least 35 times higher than human exposure. Reproductive studies in rats have shown an effect of oral administration on fertility in the form of increased preimplantation losses at dose levels of 1 mg/kg/day and above. In reproductive studies in rats, intravenous administration of ibandronic acid reduced sperm count at doses of 0.3 and 1 mg/kg/day and reduced fertility in males at a dose of 1 mg/kg/day and in females at a dose of 1.2 mg/kg/day. Other adverse reactions of ibandronic acid in reproductive toxicity studies in rats were the same as those observed for all bisphosphonates as a class. These include a decrease in the number of implantation sites, disruption of natural labor (dystocia), and an increase in visceral changes (renal pelvic ureter syndrome).

Pharmacokinetics

There was no direct relationship between the effectiveness of ibandronic acid and the concentration of the substance in the blood plasma. The concentration in blood plasma increases in a dose-dependent manner as the dose of the solution for intravenous administration increases from 0.5 to 6 mg. Similar effectiveness of ibandronic acid was confirmed with daily and intermittent use, provided that the total dose administered during the treatment period was the same.

Suction

After oral administration, ibandronic acid is rapidly absorbed from the upper gastrointestinal tract. Plasma concentrations increase dose-dependently when the dose is increased to 50 mg and significantly more when the dose is further increased. Time to reach Cmax (TCmax) - 0.5–2 hours (median - 1 hour) after administration on an empty stomach, absolute bioavailability - 0.6%. Absorption is impaired when taking the drug with food or drinks (except pure water). Concomitant consumption of food or drinks (except pure water) reduces the bioavailability of ibandronic acid by 90%. When taking ibandronic acid 60 minutes before meals, no significant decrease in bioavailability is observed. Ingestion of food or liquid less than 60 minutes after ibandronic acid reduces its bioavailability and the resulting increase in bone mineral density (BMD).

Distribution

After entering the systemic circulation, ibandronic acid quickly binds to bone tissue or is excreted in the urine. 40–50% of the amount of the drug circulating in the blood penetrates well into bone tissue and accumulates in it. Apparent final volume of distribution 90 l. Communication with blood plasma proteins when administered orally is 85% and 85–87% when administered intravenously.

Metabolism

There is no evidence that ibandronic acid is metabolized. Ibandronate does not inhibit enzymes 1A2, 2A6, 2C9, 2C19, 2D6, 2E1 and 3A4 of the cytochrome P450 system.

Removal

40–50% of an orally or intravenously administered dose absorbed into the bloodstream is bound in the bones, and the rest is excreted unchanged by the kidneys.

The unabsorbed drug is excreted unchanged in the feces.

Terminal T1/2 for 2.5 mg tablets is 10–60 hours; for tablets 150 mg and solution for intravenous administration - 10–72 hours. The concentration of the drug in the blood decreases quickly and is 10% of the maximum 8 hours after oral administration and 3 hours after intravenous administration.

The total clearance of ibandronic acid is 84–160 ml/min. Renal clearance (60 ml/min in healthy menopausal women) accounts for 50–60% of the total clearance and depends on creatinine clearance. The difference between total and renal clearance reflects the uptake of the substance into bone tissue.

Pharmacokinetics in special groups of patients

The pharmacokinetics of ibandronic acid does not depend on gender.

There were no clinically significant interracial differences in the distribution of ibandronic acid in individuals of the Southern European and Asian races. There is not enough data regarding the Negroid race.

Patients with impaired renal function. In patients with impaired renal function, the renal clearance of ibandronic acid is linearly dependent on creatinine clearance (Cl creatinine). For patients with mild or moderate renal impairment (creatinine Cl ≥30 ml/min), no dose adjustment is required.

In patients with severe renal impairment (Cl creatinine <30 ml/min) who received the drug at a dose of 10 mg orally for 21 days, the concentration of ibandronic acid in the blood plasma was 2-3 times higher than in people with normal renal function ( total clearance 129 ml/min). In severe renal impairment, the total clearance of ibandronic acid is reduced to 44 ml/min. In patients receiving the drug at a dose of 0.5 mg IV, total, renal and non-renal clearances of ibandronic acid were reduced by 67, 77 and 50%, respectively. However, an increase in systemic concentration does not impair the tolerability of the drug.

Patients with impaired liver function. There are no data on the pharmacokinetics of ibandronic acid in patients with impaired liver function. The liver does not play a significant role in the clearance of ibandronic acid, which is not metabolized but is excreted through the kidneys and by uptake into bone tissue. Therefore, for patients with impaired liver function, no dose adjustment is required.

Since, when taken orally in therapeutic concentrations, ibandronic acid weakly binds to plasma proteins (85%), it is likely that hypoproteinemia in severe liver diseases does not lead to a clinically significant increase in the concentration of the free substance in the blood.

Elderly age. The studied pharmacokinetic parameters do not depend on age. The possible decline in renal function in elderly patients should be taken into account (see section “Patients with impaired renal function” above).

Children. There are no data on the use of Bonviva® in persons under 18 years of age.

Drug interactions

For film-coated tablets

Products containing calcium and other polyvalent cations (for example aluminum, magnesium, iron), incl. milk and solid foods may interfere with the absorption of the drug; they should be consumed no earlier than 60 minutes after oral administration of Bonviva®.

Calcium supplements, antacids and medications containing polyvalent cations (eg aluminum, magnesium, iron) may interfere with the absorption of ibandronic acid and should therefore be taken no earlier than 60 minutes after taking Bonviva®.

Bisphosphonates and NSAIDs can cause irritation of the gastrointestinal mucosa. Particular caution should be exercised when using NSAIDs concomitantly with Bonviva®. When aspirin or NSAIDs were used concomitantly with Bonviva® for 1 year, the incidence of upper gastrointestinal side effects was similar.

IV ranitidine increases the bioavailability of ibandronic acid by 20%. No dosage adjustment of ibandronic acid is required when used concomitantly with H2-histamine receptor blockers or other drugs that increase gastric pH.

For solution for intravenous administration

Bonviva® is incompatible with calcium-containing solutions and other intravenous solutions.

Common to both dosage forms

Ibandronic acid does not affect the activity of the main isoenzymes of the cytochrome P450 system. At therapeutic concentrations, ibandronic acid weakly binds to plasma proteins, and therefore it is unlikely that it will displace other drugs from protein binding sites. Ibandronic acid is excreted only through the kidneys and does not undergo any biotransformation. It appears that the elimination pathway of ibandronic acid does not involve any of the transport systems involved in the elimination of other drugs.

Contraindications

For all dosage forms:

hypersensitivity to ibandronic acid or other components of the drug;

hypocalcemia (hypocalcemia should be eliminated before starting Bonviva®, as well as when prescribing all bisphosphonates used to treat osteoporosis).

For film-coated tablets, 2.5 mg and solution for intravenous administration:

pregnancy;

breastfeeding period.

Additionally for 2.5 mg film-coated tablets:

age under 18 years (lack of clinical experience of use).

Additionally for solution for intravenous administration:

severe renal impairment (serum creatinine >200 µmol/l (2.3 mg/dl) or creatinine Cl <30 ml/min).

With caution (for film-coated tablets, 2.5 and 150 mg) - severe renal impairment (Cl creatinine <30 ml/min).

Use during pregnancy and breastfeeding

Category C.

Pregnancy. During preclinical studies, no evidence of direct embryotoxic or teratogenic effects was found; at a dose of the drug exceeding the human dose by at least 35 times, no adverse effect on the development of offspring in F1 rats was detected. The adverse effects of ibandronic acid in reproductive toxicity studies in animals were the same as for all bisphosphonates: decreased embryo production, disruption of labor, increased incidence of visceral abnormalities (stenosis of the ureteropelvic segment).

There is no experience of clinical use of Bonviva® in pregnant women.

Breastfeeding period. Excreted in milk in animals. After 24 hours, the concentration of ibandronic acid in blood plasma and milk is the same and corresponds to 5% of the maximum.

It is not known whether ibandronic acid is excreted in breast milk in women.

Side effects

Common to all dosage forms

From the gastrointestinal tract: dyspepsia, diarrhea, gastritis.

From the musculoskeletal system: arthralgia, myalgia.

From the nervous system: headache, dizziness.

Body as a whole: flu-like syndrome.

From the skin and its appendages: rash.

Hypersensitivity reactions: angioedema, urticaria.

Very rarely, osteonecrosis of the jaw has been observed when ibandronic acid was prescribed.

Common for film-coated tablets

From the gastrointestinal tract: esophagitis, ulcer or stricture of the esophagus, duodenitis.

Additionally for 2.5 mg film-coated tablets:

From the skin and its appendages: urticaria.

Body as a whole: weakness, back pain.

Laboratory indicators: decreased alkaline phosphatase activity.

Additionally for 150 mg film-coated tablets

From the gastrointestinal tract: nausea, vomiting, abdominal pain, dysphagia, flatulence, gastroesophageal reflux.

From the musculoskeletal system: muscle stiffness, muscle spasm.

Additionally for solution for intravenous administration

Bonviva®, like other bisphosphonates, when administered intravenously, may cause a short-term decrease in serum calcium levels.

From the gastrointestinal tract: constipation, gastroenteritis.

From the musculoskeletal system: pain in the limbs and bones, osteoarthritis.

From the nervous system and mental sphere: insomnia, depression.

Body as a whole: weakness, reactions at the injection site, phlebitis, thrombophlebitis, nasopharyngitis, cystitis, urinary tract infections, bronchitis, upper respiratory tract infections, arterial hypertension, hypercholesterolemia, uveitis, scleritis.

Interaction

For film-coated tablets

Products containing calcium and other polyvalent cations (for example aluminum, magnesium, iron), incl. milk and solid foods may interfere with the absorption of the drug; they should be consumed no earlier than 60 minutes after oral administration of Bonviva®.

Calcium supplements, antacids and medications containing polyvalent cations (eg aluminum, magnesium, iron) may interfere with the absorption of ibandronic acid and should therefore be taken no earlier than 60 minutes after taking Bonviva®.

Bisphosphonates and NSAIDs can cause irritation of the gastrointestinal mucosa. Particular caution should be exercised when using NSAIDs concomitantly with Bonviva®. When aspirin or NSAIDs were used concomitantly with Bonviva® for 1 year, the incidence of upper gastrointestinal side effects was similar.

IV ranitidine increases the bioavailability of ibandronic acid by 20%. No dosage adjustment of ibandronic acid is required when used concomitantly with H2-histamine receptor blockers or other drugs that increase gastric pH.

For solution for intravenous administration

Bonviva® is incompatible with calcium-containing solutions and other solutions for intravenous administration.

Common to both dosage forms

Ibandronic acid does not affect the activity of the main isoenzymes of the cytochrome P450 system. At therapeutic concentrations, ibandronic acid weakly binds to plasma proteins, and therefore it is unlikely that it will displace other drugs from protein binding sites. Ibandronic acid is excreted only through the kidneys and does not undergo any biotransformation. It appears that the elimination pathway of ibandronic acid does not involve any of the transport systems involved in the elimination of other drugs.

Bonviva tab 150 mg No. 1

5 years. Do not use after the expiration date stated on the packaging.

special instructions

• Osteoporosis can be confirmed by identifying low BMD (T index <-2.0 SD) and a fracture (including a history) or low bone mineral density (T index <-2.5 SD) in the absence of a confirmed fracture.
• Before using Bonviva, hypocalcemia and other disorders of bone metabolism and electrolyte balance should be corrected. Patients should consume adequate amounts of calcium and vitamin D.
• If the patient does not receive enough calcium and vitamin D from food, they should be taken additionally in the form of nutritional supplements.
• The use of oral bisphosphonates may lead to local irritation of the mucous membrane of the upper gastrointestinal tract. Due to the possible irritating effect of the drug and the worsening of the existing underlying gastrointestinal disease, caution should be exercised when prescribing Bonviva® to patients with active pathological processes localized in the upper gastrointestinal tract (for example, established Barrett's esophagus, dysphagia, other diseases of the esophagus, gastritis, duodenitis or ulcers).
• In patients receiving treatment with oral bisphosphonates, cases of adverse events such as esophagitis, ulcers or erosions of the esophagus, rarely accompanied by bleeding or the development of further strictures or perforations of the esophagus, have been described. In some cases, adverse events were severe and required hospitalization. The risk of severe esophageal adverse events appears to be greater in patients who do not adhere to dosage regimens and/or who continue to take oral bisphosphonates after the onset of symptoms suggestive of esophageal irritation. Patients should carefully read the recommendations for taking the drug and carefully follow them.
• Clinicians should be especially alert for any signs or symptoms indicating a possible esophageal reaction, and patients should be warned to stop taking Bonviva® and seek medical attention if they experience dysphagia, pain with swallowing or chest pain, or worsening heartburn.
• When using oral bisphosphonates (post-registration surveillance), isolated cases of the development of gastric and duodenal ulcers, sometimes severe and complicated, have been described, although in clinical studies no increase in the risk of these diseases was observed.
• Because the use of NSAIDs and bisphosphonates may be accompanied by irritation of the gastrointestinal mucosa; caution should be exercised when using NSAIDs simultaneously with Bonviva®.
• Cases of osteonecrosis of the jaw have been reported with the use of bisphosphonates. Most cases have been reported in cancer patients during dental procedures, with a few cases in patients with postmenopausal osteoporosis or other diseases. Risk factors for the development of osteonecrosis of the jaw include an established diagnosis of cancer, concomitant therapy (chemotherapy, radiation therapy, corticosteroids) and other disorders (anemia, coagulopathy, infection, existing dental disease). Most reported cases have occurred with intravenous bisphosphonates, but isolated cases have occurred in patients receiving oral medications.
• Dental surgery during bisphosphonate therapy can increase the manifestations of osteonecrosis of the jaw. It is unknown whether discontinuation of bisphosphonates reduces the risk of osteonecrosis. The decision to conduct treatment must be made for each patient individually after assessing the risk/benefit ratio.
• Atypical subtrochanteric and diaphyseal femoral fractures have been reported with bisphosphonates, primarily in patients receiving long-term treatment for osteoporosis. Transverse and short oblique fractures can be localized along the entire length of the femur from the lesser trochanter to the supracondylar eminence. Atypical fractures occur spontaneously or as a result of minor injuries. In the weeks or months before a hip fracture occurs, patients experience pain in the hip or groin area, which is often accompanied by radiographic evidence of a stress fracture. Because atypical fractures are often bilateral, it is necessary to monitor the other hip in patients with a femoral shaft fracture. Poor healing of atypical fractures was noted. If an atypical fracture is suspected and pending examination results, discontinuation of bisphosphonate therapy should be considered based on an assessment of the benefit/risk ratio in each individual case.
• Patients should be advised to report any hip or groin pain during bisphosphonate therapy. If these symptoms are present, it is necessary to conduct an examination to identify an incomplete hip fracture.

Use in pediatrics

Safety and effectiveness in children and adolescents under 18 years of age have not been established.

Description

Bone resorption inhibitor for osteoporosis in postmenopausal women.

Dosage form

White or almost white, oblong, film-coated tablets, engraved “BNVA” on one side and “150” on the other; length - 13.9-14.4 mm, width - 6.9-7.4 mm, height - 4.8-5.8 mm.

Use in children

Safety and effectiveness in children and adolescents under 18 years of age have not been established.

Pharmacodynamics

Ibandronic acid is a highly active nitrogen-containing bisphosphonate, an inhibitor of bone resorption and osteoclast activity. Ibandronic acid prevents bone destruction caused by gonadal suppression, retinoids, tumors and tumor extracts in vivo. In studies in young (fast-growing) rats, ibandronic acid also inhibited endogenous bone resorption, resulting in increased bone mass compared to control animals. In animal models, ibandronic acid has been confirmed to be a potent inhibitor of osteoclast activity and does not impair bone mineralization even when administered at doses more than 5000 times higher than doses for the treatment of osteoporosis.

With long-term use of ibandronic acid in two different dosing regimens (daily or intermittent dosing with an extended period without treatment), new normal bone formation and/or an increase in mechanical strength was observed in studies in rats, dogs and monkeys, even at doses above therapeutic levels. including doses in the toxic range. The effectiveness of Bonviva® in both regimens was confirmed in the clinical study MF4411 - daily administration of 2.5 mg or intermittent administration of 20 mg of the drug over a period of 9-10 weeks without treatment led to a decrease in the incidence of fractures.

In postmenopausal women, oral administration of Bonviva® (both daily and intermittent administration of the drug with a period of 9-10 weeks without treatment) led to biochemical changes characteristic of dose-dependent inhibition of bone resorption, incl. to a decrease in the concentration of biochemical markers of bone collagen breakdown (deoxypyridinoline and cross-linked C- and N-telopeptides of type I collagen) in the urine.

After cessation of treatment, there is a return to the previous, pre-treatment, increased level of bone resorption, characteristic of postmenopausal osteoporosis.

Histological analysis of bone biopsies taken from postmenopausal women in the second and third years of treatment showed the presence of normal bone tissue, as well as the absence of mineralization defects.

In a phase 1 bioequivalence study of 72 postmenopausal women, subjects received oral Bonviva 150 mg every 28 days (4 doses total). In this study, it was found that a decrease in the concentration of cross-linked C-telopeptide type I collagen (CTX) in serum was observed already in the first 24 hours after the first dose (an average of 28%), and an average maximum decrease in concentration (of 69%). ) was observed after 6 days. After the 3rd and 4th doses, the mean maximum decrease in concentration 6 days after each dose was 74%, and 28 days after the 4th dose, the average decrease in concentration was 56%. When the drug was stopped after the 4th dose, the concentration of biochemical markers showed the cessation of the inhibitory effect of the drug on bone resorption.

Ibandronic acid does not affect the process of replenishment of the osteoclast pool. The selective effect of ibandronic acid on bone tissue is due to its high affinity for hydroxyapatite, which constitutes the mineral matrix of bone.

Ibandronic acid inhibits bone resorption and does not have a direct effect on bone formation. In postmenopausal women, it reduces the increased rate of bone turnover to reproductive age levels, which leads to a progressive increase in bone mass. Daily or intermittent administration of ibandronic acid results in a decrease in bone resorption, as demonstrated by decreased concentrations of biochemical markers of bone turnover in urine and serum, an increase in bone mineral density (BMD), and a decrease in the incidence of fractures.

The high activity and breadth of the therapeutic range provide the possibility of a flexible dosage regimen in relatively low doses and intermittent use of the drug with a long period without treatment.

Bone Mineral Density (BMD)

In a 2-year, double-blind, multicenter study (BM16549) in postmenopausal women with osteoporosis (lumbar vertebral BMD: baseline T-score below -2.5 SD), based on an increase in BMD, it was shown that prescribing Bonviva® at a dose of 150 mg once a month is at least as effective as taking the drug at a dose of 2.5 mg daily.

Data obtained in the primary analysis after the first year of the study were confirmed in the subsequent analysis after the second year of the study.

Table. Mean increase in BMD of the lumbar vertebrae, hip, femoral neck, and trochanter compared with baseline values ​​obtained after the first (primary analysis) and second year (“protocol population”—those who met the protocol conditions and completed the study) of the BM16549 study.

In addition, in a prospective analysis, it was proven that Bonviva® at a dosage regimen of 150 mg once a month is superior to Bonviva® 2.5 mg daily in terms of the degree of increase in BMD of the lumbar vertebrae (in the first year of the study p = 0.002 and in the second year of the study p < 0.001).

After the first year of the study (primary analysis), 91.3% (p=0.005) of patients receiving Bonviva® 150 mg once a month, compared with 84% of patients receiving Bonviva® 2.5 mg daily, had an increase in lumbar vertebral BMD or maintaining its original level. At the end of the second year, 93.5% (p=0.004) of patients receiving Bonviva 150 mg once a month and 86.4% of patients receiving Bonviva 2.5 mg daily had a positive response to therapy.

Regarding hip BMD values, after the first year of the study, 90% (p <0.001) of patients receiving Bonviva® 150 mg once a month, and 76.7% of patients receiving Bonviva® 2.5 mg daily, had an increase in BMD or maintaining its original value level. By the end of the second year, 93.4% (p <0.001) of patients receiving Bonviva 150 mg once a month and 78.4% of patients receiving Bonviva 2.5 mg daily had an increase in hip BMD or maintained its baseline level.

Using a more stringent criterion that included global assessment of lumbar vertebrae and hip BMD, at the end of the first year of the study, a positive response was observed in 83.9% (p <0.001) of patients receiving Bonviva® 150 mg once a month, and in 65.7 % of patients receiving Bonviva® 2.5 mg daily. By the end of the second year - in 87.1% (p <0.001) of patients receiving Bonviva® 150 mg once a month, and in 70.5% of patients receiving Bonviva® 2.5 mg daily.

Biochemical markers of bone resorption

Clinically significant reductions in serum CTX concentrations were obtained after 3, 6, 12 and 24 months of therapy. After a year of therapy with Bonviva® 150 mg once a month (primary analysis), the average reduction was 76%, and when taking the drug at a dose of 2.5 mg daily - 67%. By the end of the second year of the study, when taking Bonviva® 150 mg once a month, the average reduction was 68%, and when taking 2.5 mg daily - 62%.

A decrease in CTX concentration of more than 50% compared to the initial value was observed in 83.5% (p = 0.006) of patients receiving Bonviva® 150 mg once a month, and in 73.9% of patients receiving Bonviva® 2.5 mg daily, during the first years of research. By the end of the second year, a positive response to therapy was observed in 78.7% (p = 0.002) of patients receiving Bonviva® 150 mg once a month, and in 65.6% of patients receiving Bonviva® 2.5 mg daily.

The BM16549 study showed that Bonviva 150 mg once a month and 2.5 mg daily were at least equally effective in reducing the risk of fractures.

Preclinical safety data

In animal studies, the toxic effect was observed only at drug exposures significantly greater than the maximum drug exposure in humans, and therefore appears to be of little significance for the clinical use of the drug.

No data indicating possible carcinogenic and genotoxic activity have been identified.

Side effects

The safety of ibandronic acid (2.5 mg daily) was assessed in four placebo-controlled clinical trials (N=1251). The majority of patients participating in these studies had previously participated in the pivotal 3-year study MF4411. The overall safety profile of ibandronic acid (2.5 mg daily) in all of the above studies was similar to that of placebo.

In a 2-year study (BM16549) in postmenopausal women with osteoporosis, the overall safety profile of Bonviva 150 mg once monthly was similar to that of Bonviva 2.5 mg daily. The overall proportion of patients who experienced adverse reactions was 22.7% and 25% after one year and 2 years of taking Bonviva 150 mg once a month, respectively. In most cases, adverse reactions were mild or moderate in intensity and did not lead to discontinuation of the drug. The most common adverse reaction was arthralgia.

Adverse reactions that have a causal relationship with taking Bonviva® (according to the researchers) are distributed by organ system class and are listed below.

The following categories are used to describe the frequency of adverse reactions: common (≥1/100 and <1/10), uncommon (≥1/1000 and <1/100) and rare (≥1/10,000 and <1/1000). In each subgroup, adverse reactions are arranged in decreasing order of severity.

Table.

Adverse reactions occurring in postmenopausal women while taking Bonviva® 150 mg once a month or ibandronic acid 2.5 mg daily (data from the 3rd phase of studies BM16549 and MF4411).

Transient flu-like symptoms were usually observed after taking the first dose of Bonviva® (150 mg once a month), were characterized by a weak or moderate degree of intensity, short duration and resolved independently without adjustment of therapy. Influenza-like syndrome may include acute phase reactions or symptoms such as myalgia, arthralgia, fever, chills, fatigue, nausea, loss of appetite, or bone pain.

In clinical studies of patients with a history of gastrointestinal disease, including peptic ulcers, without recent bleeding or hospitalization, and patients with dyspepsia or reflux receiving appropriate therapy, there was no difference in the incidence of upper gastrointestinal adverse events with Bonviva® drug in various dosage regimens (2.5 mg daily and 150 mg once a month).

In the BM16549 study, after the first and second years of taking Bonviva®, there were no differences in laboratory parameters in both groups with different dosing regimens (2.5 mg daily and 150 mg once a month).

• Post-marketing surveillance

From the musculoskeletal system and connective tissues: very rarely, when prescribing ibandronic acid, osteonecrosis of the jaw was observed.

Ocular disorders: Inflammatory ocular diseases such as episcleritis, scleritis and uveitis have been reported during therapy with bisphosphonates, including ibandronic acid. In some cases, despite treatment, recovery occurred only after discontinuation of bisphosphonates.

Use during pregnancy and breastfeeding

Bonviva® should not be used during pregnancy.

There was no evidence of direct embryotoxic or teratogenic effects in rats and rabbits treated with ibandronic acid orally; no adverse effects on offspring development were found in F1 rats. The adverse effects of ibandronic acid in reproductive toxicity studies in rats were the same as for all bisphosphonates - decreased embryo production, disruption of labor (dystocia), increased incidence of visceral abnormalities (constriction of the ureteropelvic segment). No special studies have been conducted on the once-a-month regimen.

There is no experience of clinical use of Bonviva® in pregnant women.

Excreted in milk in rats. In lactating rats with intravenous administration of ibandronate in doses of 0.08 mg/kg/day, the highest concentration of ibandronic acid in breast milk was observed in the first 2 hours after intravenous administration and amounted to 8.1 ng/ml. After 24 hours, the concentration of ibandronic acid in blood plasma and milk was the same and corresponded to 5% of the maximum.

It is not known whether ibandronic acid is excreted in breast milk in women. Bonviva® should not be used during breastfeeding.

Interaction

Calcium foods and dietary supplements, antacids and oral medications containing calcium and other polyvalent cations (for example, aluminum, magnesium, iron), incl. milk and solid foods may interfere with the absorption of the drug, so they should be consumed no earlier than 60 minutes after ingestion of Bonviva®.

Pharmacokinetic studies in postmenopausal women showed the absence of any drug-drug interaction between ibandronic acid and tamoxifen or hormone replacement therapy (estrogen). There was also no evidence of drug-drug interaction with the simultaneous use of ibandronic acid and melphalan/prednisolone in patients with multiple myeloma.

Bisphosphonates and NSAIDs can cause irritation of the gastrointestinal mucosa. Particular caution should be exercised when using NSAIDs concomitantly with Bonviva®. In a clinical study of postmenopausal women with osteoporosis (BM16549) with concomitant use of acetylsalicylic acid or other NSAIDs and Bonviva® (2.5 mg daily or 150 mg once a month) for 1 year, the incidence of upper gastrointestinal side effects was the same.

In studies involving healthy volunteers (men) and postmenopausal women, IV ranitidine increased the bioavailability of ibandronic acid by 20%, probably due to a decrease in gastric acidity. However, this increase is within the normal bioavailability limits of ibandronic acid. No dosage adjustment of ibandronic acid is required when used concomitantly with histamine H2 receptor blockers or other drugs that increase gastric pH.

Because Since ibandronic acid does not inhibit the main isoenzymes of the cytochrome P450 system, and studies in rats have shown the absence of its inducing effect, the presence of clinically significant drug-drug interactions is unlikely. At therapeutic concentrations, ibandronic acid binds weakly to plasma proteins and is therefore unlikely to displace other drugs from protein binding sites. Ibandronic acid is excreted only through the kidneys and does not undergo any biotransformation. It appears that the elimination pathway of ibandronic acid does not involve any of the transport systems involved in the elimination of other drugs.

Study BM16549, involving 1,500 patients, compared dosing regimens of ibandronic acid (daily versus monthly); of these, 14% of subjects were also taking histamine H2 receptor blockers or proton pump inhibitors. The incidence of upper gastrointestinal adverse events was similar between dosing regimens (Bonviva® 150 mg once monthly and 2.5 mg daily).

Overdose

Symptoms: possible when taken orally - dyspepsia, heartburn, esophagitis, gastritis, ulcer of the upper gastrointestinal tract.

Treatment: no specific information available. Milk or antacids are used to bind ibandronic acid. Due to the risk of esophageal irritation, vomiting should not be induced and should remain in an upright standing position.

Impact on the ability to drive vehicles and operate machinery

There have been no studies on the effect of taking Bonviva® on the ability to drive a car or use other machinery. The drug causes side effects that may affect the ability to drive vehicles and use other machinery.

Directions for use and doses

Inside, intravenously.

Orally, whole, with a glass (180–240 ml) of clean water in a sitting or standing position; you should not lie down for 60 minutes after taking Bonviva®.

Film-coated tablets, 2.5 mg

2.5 mg (1 tablet) once a day 60 minutes before the first meal of the day, liquid (except water) or other medications and nutritional supplements. Do not use mineral waters that contain a lot of calcium. The tablets should not be chewed or sucked due to the possible formation of esophageal ulcers.

Film-coated tablets, 150 mg

150 mg (1 tablet) once a month (preferably on the same day of each month), 60 minutes before the first meal of the day, liquid (except water) or other drugs and nutritional supplements. The tablets should not be chewed or sucked due to possible ulceration of the upper gastrointestinal tract. Do not use mineral water, which contains a lot of calcium.

If you miss a scheduled appointment, you should take 1 tablet. Bonviva® 150 mg, if there are more than 7 days before the scheduled dose, and then take Bonviva® once a month in accordance with the established schedule. If there are less than 7 days before the next scheduled appointment, you must wait until the next scheduled appointment and then continue taking it in accordance with the established schedule, because You cannot take more than 1 tablet. in Week.

Solution for intravenous administration

IV. The drug is for intravenous use only!

Entered only by a specialist. Its intra-arterial administration or contact with surrounding tissue should be avoided.

Before administration, it is necessary to inspect the solution for the absence of foreign impurities or discoloration.

Needles should be used in combination with syringe tubes.

The syringe tube is intended for single administration only.

Standard dosage regimen

3 mg IV bolus (over 15–30 s) once every 3 months.

The patient should additionally take calcium and vitamin D.

If you miss a scheduled injection, you should give the injection as soon as possible. Further administration of the drug should be continued every 3 months after the last administration.

The drug should not be prescribed more than once every 3 months.

During treatment, renal function, serum calcium, phosphorus and magnesium levels should be monitored.

Dosing in special patient groups

Liver dysfunction. No dose adjustment is required (see section "Pharmacokinetics").

Renal dysfunction. For mild and moderately severe renal dysfunction (creatinine Cl ≥30 ml/min), no dose adjustment is required. When creatinine Cl <30 ml/min, the decision to use Bonviva® should be based on an individual assessment of the risk/benefit ratio for a particular patient (see section “Pharmacokinetics”).

Elderly age. No dose adjustment is required.

Children. Safety and effectiveness in persons under 18 years of age have not been established.

BONVIVA film-coated tablets 150 mg No. 1

Pharmacodynamics Ibandronic acid is a highly active nitrogen-containing bisphosphonate, an inhibitor of bone resorption and osteoclast activity. Ibandronic acid prevents bone destruction caused by gonadal blockade, retinoids, tumors and tumor extracts in vivo. Inhibits endogenous resorption in young (fast-growing) rats, which is manifested by higher bone mass compared to intact animals. Does not interfere with bone mineralization when administered in doses more than 5000 times higher than doses for the treatment of osteoporosis and does not affect the process of replenishment of the osteoclast pool. The selective effect of ibandronic acid on bone tissue is due to its high affinity for hydroxyapatite, which constitutes the mineral matrix of bone. Ibandronic acid inhibits bone resorption in a dose-dependent manner and does not have a direct effect on bone formation. In menopausal women, it reduces the increased rate of bone tissue turnover to the level of reproductive age, which leads to a general progressive increase in bone mass, a decrease in the breakdown of bone collagen (concentrations of deoxypyridinoline and cross-linked C- and N-telopeptides of type I collagen) in urine and blood serum , incidence of fractures and increased BMD. High activity and therapeutic range provide the possibility of a flexible dosage regimen and intermittent administration of the drug with a long period without treatment in relatively low doses. Efficacy Taking Bonviva 150 mg once a month for a year increases the average BMD of the lumbar vertebrae, hip, femoral neck and trochanter by 4.9, 3.1, 2.2 and 4.6%; IV administration of Bonviva 3 mg once every 3 months for 1 year increases the average BMD of the femur, femoral neck and trochanter by 2.4, 2.3 and 3.8%, respectively. Regardless of the duration of menopause and the degree of initial bone loss, Bonviva resulted in a significantly greater change in BMD than placebo. The effect of treatment within a year, defined as an increase in BMD, is observed in 83.9% (when taking film-coated tablets) and 92.1% (when administered intravenously) of patients. Biochemical markers of bone resorption Film-coated tablets, 2.5 mg. Biochemical markers of bone resorption (urinary concentrations of type I procollagen C-terminal peptide (CTX) and serum osteocalcin) decline to their levels during reproductive age; the maximum reduction is observed after 3-6 months of treatment. Just one month after starting the use of Bonviva 2.5 mg daily and 20 mg intermittently, a clinically significant reduction in biochemical markers of bone resorption was achieved by 50 and 78%, respectively; Moreover, a slight decrease in these indicators was noted after a week of treatment. A clinically significant decrease in biochemical markers of bone resorption (urinary CTX concentrations) is observed one month after the start of treatment. Bonviva 2.5 mg daily for the prevention of postmenopausal osteoporosis (study MF4499) increased mean lumbar spine BMD by 1.9% compared with baseline. Regardless of the duration of menopause and the degree of initial loss of basic bone tissue, the use of Bonviva leads to a significantly more pronounced change in BMD of the lumbar vertebrae. When using Bonviva, the treatment effect, defined as an increase in BMD compared to the baseline, is observed in 70% of patients. Film-coated tablets, 150 mg and solution for intravenous administration. A 28% decrease in serum CTX concentration was noted within 24 hours after the first dose of 150 mg Bonviva, with a maximum decrease of 68% after 6 days. After the third and fourth doses of Bonviva 150 mg, the maximum decrease in serum CTX by 74% was observed after 6 days. 28 days after taking the fourth dose, a decrease in the suppression of biochemical markers of bone resorption was noted to 56%. Clinically significant reductions in serum CTX were obtained after 3, 6 and 12 months of therapy. After a year of therapy with Bonviva 150 mg, the reduction was 76%; compared with the initial value, when using 3 mg intravenously - 58.6%. A decrease in CTX of more than 50% compared to the initial value was observed in 83.5% of patients receiving Bonviva 150 mg once every 28 days. Pharmacokinetics There was no direct relationship between the effectiveness of ibandronic acid and the concentration of the substance in the blood plasma. The concentration in blood plasma increases in a dose-dependent manner as the dose of the solution for intravenous administration increases from 0.5 to 6 mg. Similar effectiveness of ibandronic acid was confirmed with daily and intermittent use, provided that the total dose administered during the treatment period was the same. Absorption Following oral administration, ibandronic acid is rapidly absorbed from the upper gastrointestinal tract. Plasma concentrations increase dose-dependently when the dose is increased to 50 mg and significantly more when the dose is further increased. Time to reach Cmax (TCmax) - 0.5–2 hours (median - 1 hour) after administration on an empty stomach, absolute bioavailability - 0.6%. Absorption is impaired when taking the drug with food or drinks (except pure water). Concomitant consumption of food or drinks (except pure water) reduces the bioavailability of ibandronic acid by 90%. When taking ibandronic acid 60 minutes before meals, no significant decrease in bioavailability is observed. Ingestion of food or liquid less than 60 minutes after ibandronic acid reduces its bioavailability and the resulting increase in bone mineral density (BMD). Distribution Once in the systemic circulation, ibandronic acid is rapidly bound to bone tissue or excreted in the urine. 40–50% of the amount of the drug circulating in the blood penetrates well into bone tissue and accumulates in it. Apparent final volume of distribution 90 l. Communication with blood plasma proteins when administered orally is 85% and 85–87% when administered intravenously. Metabolism There is no evidence that ibandronic acid is metabolized. Ibandronate does not inhibit enzymes 1A2, 2A6, 2C9, 2C19, 2D6, 2E1 and 3A4 of the cytochrome P450 system. Excretion: 40–50% of an orally or intravenously administered dose absorbed into the bloodstream is bound in the bones, and the rest is excreted unchanged by the kidneys. The unabsorbed drug is excreted unchanged in the feces. Terminal T1/2 for 2.5 mg tablets is 10–60 hours; for tablets 150 mg and solution for intravenous administration - 10–72 hours. The concentration of the drug in the blood decreases quickly and is 10% of the maximum 8 hours after oral administration and 3 hours after intravenous administration. The total clearance of ibandronic acid is 84–160 ml/min. Renal clearance (60 ml/min in healthy menopausal women) accounts for 50–60% of the total clearance and depends on creatinine clearance. The difference between total and renal clearance reflects the uptake of the substance into bone tissue. Pharmacokinetics in special groups of patients The pharmacokinetics of ibandronic acid does not depend on gender. There were no clinically significant interracial differences in the distribution of ibandronic acid in individuals of the Southern European and Asian races. There is not enough data regarding the Negroid race. Patients with impaired renal function. In patients with impaired renal function, the renal clearance of ibandronic acid is linearly dependent on creatinine clearance (Cl creatinine). For patients with mild or moderate renal impairment (creatinine Cl ≥30 ml/min), no dose adjustment is required. In patients with severe renal impairment (Cl creatinine Patients with impaired liver function. There are no data on the pharmacokinetics of ibandronic acid in patients with impaired liver function. The liver does not play a significant role in the clearance of ibandronic acid, which is not metabolized, but is excreted through the kidneys and by uptake in bone tissue. Therefore, for patients with impaired liver function, dose adjustment is not required. Since when taken orally in therapeutic concentrations, ibandronic acid weakly binds to plasma proteins (85%), it is likely that hypoproteinemia in severe liver diseases does not lead to clinically significant increase in the concentration of free substance in the blood. Elderly. The studied pharmacokinetic parameters do not depend on age. A possible decrease in renal function in elderly patients should be taken into account. Children. There are no data on the use of Bonviva in persons under 18 years of age.

Overdose

For film-coated tablets

Symptoms: dyspepsia, heartburn, esophagitis, gastritis, ulcers, hypocalcemia, hypophosphatemia

Treatment: no specific information available. Milk or antacids are used to bind Bonviva®. Due to the risk of esophageal irritation, vomiting should not be induced and the patient should remain in an upright standing position.

For solution for intravenous administration

Symptoms: hypocalcemia, hypophosphatemia, hypomagnesemia.

Treatment: no specific information available. Clinically significant decreases in serum calcium, phosphate and magnesium can be corrected by intravenous administration of calcium gluconate, potassium gluconate or sodium phosphate and magnesium sulfate, respectively. Dialysis is ineffective if prescribed 2 hours after drug administration.

special instructions

Risk factors for the development of postmenopausal osteoporosis and fractures include a family history, previous bone fractures, early menopause, active bone turnover, low BMD (at least 1.0 SD less than the average BMD at reproductive age), frail physique, and women belonging to the Southern European and Asian race, smoking. These factors are of great importance when deciding whether to prescribe Bonviva® film-coated tablets 2.5 mg for the prevention of osteoporosis.

Osteoporosis can be confirmed by identifying low BMD (T index <-2.0 SD (Standard deviation) and/or by the presence of an osteoporotic fracture (including a history) or low bone mineral density (T index < -2.5 SD) in the absence of a confirmed fracture.

Before using Bonviva®, hypocalcemia and other disorders of bone metabolism and electrolyte balance should be corrected. Patients should consume adequate amounts of calcium and vitamin D.

If the patient does not receive enough calcium and vitamin D from food, then they should be additionally taken in the form of nutritional supplements.

When taken orally, the side effects of the drug are usually mild or moderate. A transient flu-like syndrome is observed after taking the first dose and resolves independently without adjustment of therapy. There was no increase in the incidence of upper gastrointestinal adverse effects in patients with gastrointestinal diseases (including peptic ulcer without bleeding or hospitalization, dyspepsia or reflux disease).

The use of oral bisphosphonates is often accompanied by difficulty swallowing, esophagitis and the formation of ulcers of the esophagus and stomach, so special attention must be paid to following the recommendations for taking the drug (sitting or standing position for 60 minutes after administration).

If signs and symptoms of possible damage to the esophagus appear (the appearance or worsening of swallowing difficulties, pain when swallowing, chest pain, heartburn), you should stop taking Bonviva® and consult a doctor.

Post-marketing experience with Bonviva® is limited.

Serum creatinine should be determined before each injection.

Osteonecrosis of the jaw has been reported when bisphosphonates were prescribed. Most cases have been reported in patients with cancer during dental procedures, with a few cases in patients with postmenopausal osteoporosis or other diseases. Risk factors for the development of osteonecrosis of the jaw include an established diagnosis of cancer, concomitant therapy (chemotherapy, radiation therapy, corticosteroids) and other disorders (anemia, coagulopathy, infection, gum disease). Most cases were observed with intravenous bisphosphonates, but isolated cases were observed in those receiving oral drugs.

Dental surgery during bisphosphonate therapy can increase the manifestations of osteonecrosis of the jaw. It is not known whether discontinuation of bisphosphonates reduces the risk of osteonecrosis. The decision to conduct treatment must be made for each patient individually after assessing the risk/benefit ratio.

Bonviva®

Osteoporosis can be confirmed by identifying low BMD (T index < -2 SD [Standard deviation]), fracture (including a history) or low bone mineral density (T index < -2.5 SD) in the absence confirmed fracture.

Hypocalcemia

Before using Bonviva®, hypocalcemia and other disorders of bone metabolism and electrolyte balance should be corrected. Patients should consume sufficient amounts of calcium and vitamin D. If the patient does not receive enough calcium and vitamin D from food, then additional calcium and vitamin D should be taken in the form of dietary supplements.

Anaphylactic reactions

Cases of anaphylactic reactions/shock, including death, have been reported in patients treated with intravenous ibandronic acid.

During intravenous administration of Bonviva®, the patient's condition should be monitored and appropriate medical care should be available. If an anaphylactic or other severe hypersensitivity/allergic reaction is detected, the infusion should be interrupted immediately and appropriate treatment should be initiated.

Patients with heart failure

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

Patients with kidney failure

Serum creatinine should be determined before each injection. Patients with underlying medical conditions receiving nephrotoxic therapy who may experience deterioration in renal function should be closely monitored.

Osteonecrosis of the jaw

When bisphosphonates were used in patients with cancer, osteonecrosis of the jaw was observed, most often associated with tooth extraction and/or local infection (in particular, osteomyelitis). Osteonecrosis of the jaw developed mainly due to intravenous use of bisphosphonates, which was often accompanied by chemotherapy and the use of glucocorticosteroids.

Osteonecrosis of the jaw has also been reported with oral bisphosphonates for the treatment of osteoporosis.

In the presence of associated risk factors such as cancer, radiation or chemotherapy (including angiogenesis inhibitors), use of glucocorticosteroids, and poor oral hygiene, a dental examination and appropriate preventive treatment are recommended before prescribing bisphosphonates.

During treatment with bisphosphonates, invasive dental procedures should be avoided.

Dental surgery during bisphosphonate therapy may increase the manifestation of osteonecrosis of the jaw. It is not known whether discontinuation of bisphosphonates reduces the risk of osteonecrosis. The decision to conduct treatment must be made for each patient individually after assessing the risk/benefit ratio.

Cases of osteonecrosis of other maxillofacial areas, including the external auditory canal, have been reported in patients receiving bisphosphonate therapy, including ibandronic acid. Additional risk factors may include repeated minor injuries (eg, regular use of Q-tips). Risk factors for the development of osteonecrosis coincided with those for osteonecrosis of the jaw. Patients receiving bisphosphonates who have hearing impairment, including chronic ear infections, should be monitored for the development of osteonecrosis.

Atypical hip fractures

Atypical subtrochanteric and diaphyseal femoral fractures have been reported in patients receiving bisphosphonates, primarily in patients receiving long-term treatment for osteoporosis.

Transverse and short oblique fractures can be localized along the entire length of the femur from the lesser trochanter to the supracondylar eminence. Atypical fractures occur spontaneously or as a result of minor injuries. In the weeks or months before a complete hip fracture occurs, some patients experience hip or groin pain, which is often accompanied by radiographic evidence of a stress fracture. Because atypical fractures are often bilateral, it is necessary to monitor the other hip in patients with a femoral shaft fracture. Poor healing of atypical fractures was noted.

If an atypical fracture is suspected and pending examination results, discontinuation of bisphosphonate therapy should be considered based on an assessment of the benefit/risk ratio in each individual case. Patients should be advised to report any hip or groin pain during bisphosphonate therapy. If these symptoms are present, it is necessary to conduct an examination to identify an incomplete hip fracture.

When taking bisphosphonates, including Bonviva®, severe pain syndrome may occur: pain in the joints, bones and muscles. Pain occurred both within 24 hours and several months after starting the drug; in most patients it resolved after stopping therapy; in some of them, symptoms recurred after re-administration of the same or a different drug.

Destruction Instructions

Destruction of syringes/needles

When using and disposing of syringes and other medical products containing needles, the following rules should be strictly observed:

- do not reuse syringes and needles;

— all used needles and syringes should be placed in containers (disposable, puncture-resistant containers);

— it is necessary to store the container in places inaccessible to children;

— Disposal of needle containers with household waste should be avoided;

- Containers filled with syringes/needles should be disposed of according to local regulations or as directed by a physician.

Patients should be provided with puncture-resistant containers for disposal of syringes and needles at home.

Destruction of unused medicinal product or after expiration date

The release of medicinal products into the environment should be minimized. Bonviva® should not be disposed of with wastewater or household waste. Where possible, special systems should be used to dispose of medications.