Instructions for use BONVIVA tablets

Compound

The tablets contain the active ingredient ibandronic acid (2.5 mg or 150 mg), as well as additional ingredients: povidone, anhydrous colloidal silicon dioxide, lactose monohydrate, stearic acid, crospovidone, MCC.
The tablet shell consists of titanium dioxide, hypromellose, talc, macrogol 6000. Bonviva IV contains the active substance ibandronic acid (3 mg), as well as auxiliary ingredients: sodium chloride, sodium acetate trihydrate, glacial acetic acid, water.

Release form

The drug Bonviva is produced in the form of tablets and a solution for intravenous administration.

• 2.5 mg tablets are film-coated, slightly biconvex, oval, white or slightly white in color. “IT” is engraved on one side of the tablet and “L 3” on the other side. Tablets containing 2.5 mg of ibandronic acid, 14 pcs in a blister, two blisters in a pack.
• Bonviva 150 mg tablets are film-coated, oblong, oval, white or slightly white in color. “BNVA” is engraved on one side of the tablet and “150” on the other side. Tablets containing 150 mg of ibandronic acid, 1 or 3 pcs in a blister, one blister in a pack.
• The medicine in the form of a solution is a colorless transparent liquid. It is contained in a special 3 ml syringe tube; the kit also includes a sterile needle. The syringe is placed in a cardboard box.

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.

pharmachologic effect

The component ibandronic acid is a highly active bisphosphonate containing nitrogen. This substance is an inhibitor of bone resorption and osteoclast activity. Under its influence, bone destruction is prevented, which is caused by blockade of the function of the sex glands, retinoids , tumors .

The product does not disrupt the process of bone mineralization and does not affect the replenishment of the osteoclast pool. The active component selectively affects bone tissue, which is due to its significant affinity for hydroxyapatite , which makes up the mineral matrix of bone.

The active component of the drug Bonviva stops bone resorption and does not directly affect the process of bone tissue formation. When taking drugs during menopause , there is a decrease in the rate of bone tissue renewal to the level observed during reproductive age. As a result, there is a general increase in bone mass, the breakdown of bone collagen decreases, and the incidence of fractures decreases.

Due to the high activity of the drug and the wide therapeutic range, flexible dosing and intermittent administration of Bonviva with a long period without treatment is permissible.

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.

Pharmacokinetics and pharmacodynamics

There was no direct dependence of the effect of ibandronic acid on the concentration of the component in plasma.

After oral administration, rapid absorption of ibandronic acid is observed, absorption occurs in the upper gastrointestinal tract. There is a dose-dependent increase in the concentration of the active substance in plasma. The highest concentration is achieved 0.5–2 hours after the drug has been taken on an empty stomach. The level of absolute bioavailability is 0.6%. When taken with food, the absorption process is disrupted; you can take the tablets with clean water. When taken simultaneously with food, the level of bioavailability decreases by 90%. When using the product 1 hour before meals, the level of bioavailability does not decrease.

After the substance enters the bloodstream, it quickly binds to bone tissue or is excreted from the body. Approximately 40–50% of the substance that circulates in the blood penetrates the bone tissue and accumulates.

It binds to blood proteins by 85% when taken orally and by 85–87% when taking Bonviva intravenously.

There is no evidence that the active substance is metabolized.

Approximately half the dose is bound in bone tissue, the part that remains unbound is excreted unchanged in the urine.

The half-life for 2.5 mg tablets is 10-60 hours, for Bonviva 150 mg and IV solution - 10-72 hours. After oral administration, 8 hours later and 3 hours after IV administration, the concentration of the active substance decreases to 10%.

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.

Contraindications

The drug Bonviva in all forms is contraindicated in the following cases:

• high sensitivity to drug ingredients;
• hypocalcemia (must be eliminated before starting treatment).

Contraindications for Bonviva 2.5 mg and IV solution:

• pregnancy and breastfeeding;
• patient age under 18 years (tablets);
• severe renal dysfunction (solution).

Prescribe the medicine with caution for acute conditions in the stomach and esophagus, duodenitis , Barrett's esophagus , dysphagia , gastritis .

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.

Side effects

During treatment, a number of side effects common to all forms of Bonviva may occur:

• digestive system: gastritis , dyspepsia , diarrhea ;
• nervous system: dizziness , headaches ;
• skin: rash ;
• allergic manifestations: urticaria , angioedema ;
• other manifestations: flu-like syndrome, in very rare cases - osteonecrosis of the jaw .

Side effects when using Bonviva tablets:

• digestive system: duodenitis , ulcer or stricture of the esophagus , esophagitis ;
• general manifestations: weakness, back pain.

Side effects when using Bonviva 150 mg tablets:

• digestive system: dysphagia , vomiting , nausea , abdominal pain, reflux , flatulence ;
• musculoskeletal system: muscle spasm, muscle stiffness.

Side effects when using Bonviva IV:

• short-term decrease in calcium levels in the blood;
• digestive system: gastroenteritis , constipation ;
• musculoskeletal system: osteoarthritis , pain in the limbs, bones;
• nervous system: depression , insomnia ;
• general manifestations: reactions at the injection site, weakness, phlebitis , thrombophlebitis , cystitis , nasopharyngitis , bronchitis , urinary tract infections, scleritis , upper respiratory tract infections, hypertension , uveitis , hypercholesterolemia .

Instructions for use of Bonviva (Method and dosage)

Bonviva tablets, instructions for use

The drug in tablet form should be taken orally with water (a full glass), in a standing or sitting position. You should not drink mineral water because it contains a large amount of calcium. After taking the tablet, do not lie down for 60 minutes. Do not suck or chew the tablet, as the risk of ulcers on the esophagus increases.

Bonviva 2.5 mg should be taken once a day, one tablet. This should be done 1 hour before the first meal of the day.

Bonviva 150 mg should be taken 1 tablet once a month. You should take the tablet on the same day. If the next dose was missed, you need to take the pill as soon as the opportunity presents itself. Next, you need to follow the dosage schedule established by your doctor. It is strictly forbidden to take two 150 mg tablets per week.

Bonviva solution, instructions for use

Used for intravenous use only. Do not allow the medicine to get into surrounding tissues. For administration, use those needles that are included with the syringe tube. It is indicated to administer 3 mg intravenously as a bolus (infusion lasts 15–30 s) once every three months. Additionally, taking calcium and vitamin D .

If an injection is missed, it should be given as soon as possible. Further administration of the drug is continued 3 months after the last administration. The product should not be administered more often than once every three months.

During the treatment period, it is important to monitor the levels of phosphorus, magnesium, calcium in the serum, as well as control of kidney function.

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.

Overdose

In case of an overdose of tablets, the patient may experience esophagitis , gastritis , hypocalcemia , dyspepsia , heartburn , hypophosphatemia , and ulcers .

In order to bind ibandronic acid, you need to take antacids and milk. Do not induce vomiting, as there is a risk of irritation of the esophagus. You need to remain in a standing position.

In case of an overdose of a solution for intravenous administration, hypophosphatemia , hypocalcemia , and hypomagnesemia . of calcium gluconate , potassium or magnesium sulfate and sodium phosphate is indicated Dialysis is not effective.

Interaction

Interaction of Bonviva tablets may occur in the following cases:

• Absorption of the active substance of Bonviva may interfere with the intake of calcium-containing products, as well as products containing iron , magnesium , and aluminum . After oral administration of the drug, they can be taken no earlier than 1 hour later. Similarly, you need to take nutritional supplements containing these minerals.
• Taking bisphosphonates and NSAIDs can cause irritation of the gastrointestinal mucosa. This combination must be practiced very carefully.
• Intravenous administration of ranitidine increases the level of bioavailability of ibandronic acid by 20%.

Interactions with Bonviva solution may occur in the following cases:

• The solution is incompatible with solutions that contain calcium, as well as with other solutions for intravenous administration.

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.

special instructions

Before using Bonviva, you need to take into account all risk factors for fractures and postmenopausal osteoporosis .

Before starting to use the drug, it is necessary to correct all disturbances in electrolyte balance, as well as bone metabolism, in particular hypocalcemia . For this purpose, the patient is prescribed a sufficient amount of vitamin D. It is important that the patient receives enough calcium and vitamin D during treatment with Bonviva.

When taking drugs orally, side effects are usually mild or moderate. The manifestation of influenza-like syndrome can be observed after the first dose; it goes away without adjusting the dosage of the drug.

It is important to take into account all recommendations for taking the medication in order to avoid side effects such as ulcers , swallowing problems , and esophagitis . If such symptoms occur, you should stop treatment and consult a doctor.

Serum creatinine should be monitored before each injection.

Cases of osteonecrosis of the jaw when bisphosphonates were prescribed against the background of cancer. The risk of such manifestations increases with surgical intervention to treat dental diseases.

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.

Bonviva's analogs

Level 4 ATC code matches:
Tevanat

Alendronic acid

Rizendros

Zolerix

Aklasta

Forosa

Xydiphone

Zometa

Ibandronic acid

Fosamax

Ostalon

Alendronate

Bonviva analogues are medicines that contain the same active ingredient. These are the drugs Bondronat , Ossika , Bandron-Zdorovye , Ibandronat .

There are also a number of drugs that have a similar effect on the body. These are the drugs Kalcemin , Veprena , Aquadetrim , Andriol , Bivalos , etc.

Bonviva price, where to buy

You can buy the drug in pharmacies or order it online. The price of Bonviva in tablets is from 1,700 rubles per 1 tablet. 150 mg. The price of Bonviva injections is on average 5,000 rubles. per syringe tube 3 mg.

• Online pharmacies in RussiaRussia
• Online pharmacies in UkraineUkraine
• Online pharmacies in KazakhstanKazakhstan

LuxPharma* special offer

• Bonviva tablets 150 mg No. 3 (Hoffmann–La Roche)
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• Bonviva 150 mg N3 tablets Hoffman-La Roche Ltd, Switzerland
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• Bonviva 150 mg N1 tablets Hoffman-La Roche Ltd, Switzerland

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• Bonviva 3 mg 3 ml solution in syringe

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