Bondronat, 50 mg, film-coated tablets, 28 pcs.

Release form and composition

• concentrate for the preparation of solution for infusion: transparent colorless liquid (2 ml in colorless glass bottles, 1 bottle in a cardboard box);
• film-coated tablets: oblong, white or almost white, with L2 engraved on one side and IT on the other (7 pieces in blisters, 4 blisters in a cardboard box).

1 ml of concentrate contains:

• active substance: sodium ibandronate monohydrate, its content in terms of ibandronic acid – 1 mg;
• excipients: acetic acid 99%, sodium chloride, water for injection, sodium acetate trihydrate.

1 tablet contains:

• active substance: sodium ibandronate monohydrate, its content in terms of ibandronic acid is 50 mg;
• excipients: stearic acid, microcrystalline cellulose, povidone (K25), lactose monohydrate, colloidal silicon dioxide (anhydrous), crospovidone;
• shell composition: macrogol 6000, titanium dioxide (E171), hypromellose and talc or ready-made mixture Opadry 00A28646.

Contraindications

Absolute contraindications for both dosage forms of Bondronat:

• hypocalcemia;
• pregnancy and breastfeeding;
• age under 18 years;
• hypersensitivity to any component of the drug.

Additional contraindications for tablets:

• the patient's inability to stand or sit for 1 hour;
• the presence of a lesion of the esophagus, which can lead to a delay in its emptying (for example, achalasia, stricture).

Relative contraindications:

• creatinine clearance <50 ml/min;
• hypersensitivity to other bisphosphonates;
• simultaneous use of non-steroidal anti-inflammatory drugs - only for tablets.

Directions for use and dosage

Concentrate for the preparation of solution for infusion

In this form, Bondronat is used in a hospital setting.

For metastatic bone lesions, the drug is administered intravenously. Before administration, the concentrate is diluted in 100 ml of 5% dextrose solution or 0.9% sodium chloride solution. Single dose – 6 mg. The duration of administration is at least 15 minutes. Frequency of use: once every 3–4 weeks.

For hypercalcemia caused by malignant neoplasms, the drug is administered intravenously as a single infusion lasting 1–2 hours. Before administration, the concentrate is diluted in 500 ml of 5% dextrose solution or 0.9% sodium chloride solution.

Treatment of hypercalcemia begins after adequate hydration with 0.9% sodium chloride solution. The dose of Bondronat depends on the severity of hypercalcemia and the type of malignant disease. As a rule, for severe hypercalcemia (albumin-corrected serum calcium ≥ 3 mmol/l or ≥ 12 mg/dl), the drug is prescribed at a dose of 4 mg, for moderate hypercalcemia (albumin-corrected serum calcium < 3 mmol/l or < 12 mg/dl). dl) – 2 mg. In clinical studies, a maximum dose of 6 mg was used, but it did not lead to an increase in effect. It usually takes 7 days for serum calcium levels to decrease to normal levels. The average time for relapse of hypercalcemia (repeated increase in the concentration of albumin-corrected serum calcium more than 3 mmol/l), according to clinical studies, is 18–19 days when using Bondronat in doses of 2 and 4 mg, 26 days when using a dose of 6 mg.

In case of insufficient effectiveness of therapy or relapse, repeated administration of the drug is possible. Repeat infusion due to recurrence of hypercalcemia is required in a limited number of patients.

Elderly patients and patients with impaired liver function do not require dose adjustment.

There is also no need to adjust the dose for bone metastases in patients with mild renal impairment or a creatinine clearance (CC) of 50–80 ml/min.

For metastatic bone damage due to breast cancer, patients with moderate (creatinine clearance 30–50 ml/min) and severe (creatinine clearance <30 ml/min) renal impairment are recommended to use the following dosage regimen depending on the plasmatic clearance:

• 50–80 ml/min: ibandronic acid dose – 6 mg, infusion volume – 100 ml, infusion duration – 15 minutes;
• 30–49 ml/min: ibandronic acid dose – 4 mg, infusion volume – 500 ml, infusion duration – 60 minutes;
• < 30 ml/min: ibandronic acid dose – 2 mg, infusion volume – 500 ml, infusion duration – 60 minutes.

The drug is administered once every 3–4 weeks. To dilute the concentrate, use a 0.9% sodium chloride solution or a 5% dextrose solution.

In patients with CC < 50 ml/min, the safety and effectiveness of an infusion lasting 15 minutes has not been studied.

After dilution of the concentrate, the infusion solution is physically and chemically stable for 24 hours. However, from a microbiological point of view, the prepared solution should be used immediately. If this is not possible, the solution for intravenous administration should be stored at a temperature of 2–8 ° C, but not more than 24 hours and provided that the dilution was made under controlled and validated aseptic conditions.

Before administration, the physician must inspect the solution for the absence of foreign visible particles.

Film-coated tablets

A single dose is 50 mg (1 tablet).

Bondronate should be taken orally once a day, in the morning on an empty stomach - at least 30 minutes before the first meal/liquid (except drinking water) or other nutritional supplements and medications. The tablets must be taken in a sitting or standing position: swallowed whole, without chewing or dissolving (since the formation of oropharyngeal ulcerations is possible), washed down with plenty of plain clean water (180–240 ml).

Do not take tablets with mineral water containing a lot of calcium.

Do not lie down for 60 minutes after taking the drug.

Elderly patients, patients with impaired liver function and patients with mildly impaired renal function (creatinine clearance 50–80 ml/min) do not require dose adjustment.

For moderately severe renal dysfunction (creatinine clearance 30–50 ml/min), Bondronate should be taken once every 2 days, for severe impairment (creatinine clearance < 30 ml/min) – once every 7 days.

Pharmacological properties of the drug Bondronat

Pharmacodynamics Ibandronic acid (3-(N-Methyl-3-(methylpentylamino)-1-hydroxypropane)-1,1-diphosphonic acid monosodium monohydrate) is a highly active nitrogen-containing bisphosphonate, an inhibitor of bone resorption and osteoclast activity. It has a specific selective effect on bone tissue due to its high affinity for the mineral components of bone tissue. Inhibits the activity of osteoclasts, reduces the incidence of skeletal complications in malignant diseases. Ibandronic acid reduces osteoclast-associated release of tumor growth factors, inhibits the spread and invasion of tumor cells, and exhibits a synergistic effect with taxanes in vitro . Ibandronic acid prevents bone destruction caused by blockade of gonadal function, retinoids, tumor processes and tumor extracts administered in vivo . Inhibits endogenous bone resorption and promotes the excretion of radioactive tetracycline, which was previously introduced into the bone tissue. Does not interfere with bone mineralization when administered in doses significantly higher than pharmacologically effective ones. In hypercalcemia, the inhibitory effect of ibandronic acid on tumor-induced osteolysis and on hypercalcemia accompanying the tumor process is accompanied by a decrease in the level of calcium in the blood serum and calcium excretion in the urine. In most cases, calcium levels in the blood return to normal within 4–7 days after administration of the drug. Ibandronic acid prevents the development of new ones and reduces the growth of existing bone metastases, resulting in a reduction in the incidence of skeletal complications, pain intensity, the need for radiation therapy and surgical interventions for metastatic processes in bone tissue, which significantly improves the quality of life of patients. Ibandronic acid dose-dependently inhibits tumor osteolysis, as determined by markers of bone resorption (pyridinoline, deoxypyridinoline). Pharmacokinetics Absorption. After oral administration, ibandronic acid is rapidly absorbed from the upper gastrointestinal tract. Maximum concentrations in blood plasma are achieved after 30 minutes - 2 hours (on average after 1 hour) when taken on an empty stomach, absolute bioavailability is about 0.6%. Absorption is impaired when taken simultaneously with food or drinks (except plain water). Bioavailability is reduced by approximately 90% when consuming a normal breakfast compared to bioavailability when taking the drug on an empty stomach. When taking ibandronic acid 60 minutes before meals, there was no significant decrease in bioavailability. After intravenous administration, ibandronic acid quickly binds to bone tissue or is excreted in the urine. Distribution. After initial systemic distribution, 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. About 85% binds to blood plasma proteins. Metabolism. There is no data on the metabolism of ibandronic acid in animals and humans. Excretion. Ibandronic acid is eliminated from the systemic circulation by bone absorption (40–50%), the remaining amount is excreted unchanged through the kidneys. That part of ibandronic acid that is not absorbed is excreted unchanged in the feces. The half-life is 10–60 hours. The initial level of the drug in the blood plasma decreases rapidly and reaches 10% of the maximum value within 8 hours after oral administration. When ibandronic acid was administered intravenously at 4-week intervals for 48 weeks in patients with metastatic bone lesions, no systemic accumulation of the drug was observed. The total clearance of ibandronic acid is 84–160 ml/min. Renal clearance (about 60 ml/min in healthy postmenopausal women) accounts for 50–60% of the total and depends on creatinine clearance. The difference between total and renal clearance reflects the absorption of the drug into bone tissue. Pharmacokinetics in special cases. Floor. The bioavailability and pharmacokinetics of ibandronic acid do not depend on gender. Race. There are no data on clinically significant interethnic differences between Mongoloid and Caucasian patients regarding the distribution of ibandronic acid. There is insufficient data on black patients. Patients with renal failure. The renal clearance of ibandronic acid in patients with different stages of renal failure is linearly dependent on creatinine clearance. In patients with moderately severe renal impairment (creatinine clearance ≥30 ml/min), the dose of the drug does not need to be adjusted. In individuals with severe renal impairment (creatinine clearance ≤30 ml/min), who used orally 10 mg of ibandronic acid per day for 21 days, an increase in the concentration of the drug in the blood plasma was noted by 2-3 times compared with patients with unchanged function kidneys (creatinine clearance - 129 ml/min). The total clearance of ibandronic acid was reduced to 44 ml/min in subjects with severe renal impairment. After a single intravenous administration of 6 mg ibandronate (infusion over 15 minutes), the AUC0-24 value increased by 14 and 86%, respectively, in individuals with mild (average creatinine clearance - 68.1 ml/min) and moderately severe (average creatinine clearance - 68.1 ml/min) - 41.2 ml/min) renal failure compared with healthy volunteers (average creatinine clearance - 120 ml/min). The mean maximum plasma concentration did not increase in patients with mild renal impairment and increased by 12% in patients with moderate renal impairment. There is no evidence of impaired tolerance when increasing the dose of the drug. However, adjustment of the dose or timing of administration is necessary for patients with metastatic bone lesions from breast cancer. About 37% of ibandronate is eliminated from the body during standard 4-hour hemodialysis. Patients with liver failure. There are no data on the pharmacokinetics of ibandronic acid in patients with impaired liver function. The liver does not take a significant part in the clearance of ibandronic acid, which is not metabolized, but is excreted through the kidneys and by absorption into bone tissue. Thus, in patients with impaired liver function, no dose adjustment of the drug is required. Since the binding of ibandronic acid at therapeutic concentrations to plasma proteins is insignificant (85%), it is unlikely that hypoproteinemia in severe liver disease will lead to a clinically significant increase in the concentration of the free drug. Elderly patients. The studied pharmacokinetic parameters do not depend on age. Because kidney function declines with age, this is the only factor that needs to be considered (see Patients with Renal Failure). Children. There is no data on the use of Bondronat in patients under 18 years of age.

Side effects

Concentrate for the preparation of solution for infusion

When Bondronat is administered at a dose of 6 mg once every 4 weeks for the treatment of metastatic bone lesions, the following side effects are observed:

• from the digestive system: often (from ≥ 1% to < 10%) – diarrhea;
• from the nervous system: often – headache;
• from the musculoskeletal system: often – myalgia;
• from the body as a whole: often – asthenia, influenza-like syndrome;
• from the organ of vision*: inflammatory diseases of the eyes (scleritis, episcleritis, uveitis);
• from the musculoskeletal system and connective tissue*: very rarely (<0.01%) – osteonecrosis of the jaw.

*These side effects were observed during a post-marketing study.

When Bondronat is administered in doses of 2 and 4 mg for the treatment of hypercalcemia caused by malignant diseases, fever very often occurs.

Film-coated tablets

Clinical researches:

• from the metabolic side: often – hypocalcemia;
• from the digestive system: often – dyspepsia.

Post-marketing surveillance:

• from the organ of vision: inflammatory diseases of the eyes (scleritis, episcleritis, uveitis);
• from the musculoskeletal system and connective tissue: very rarely - osteonecrosis of the jaw.

special instructions

Before prescribing Bondronat, electrolyte balance (including hypocalcemia) and other disorders of bone metabolism should be corrected.

During therapy, it is necessary to monitor renal function, serum calcium, magnesium, and phosphorus.

During treatment, patients are advised to additionally consume vitamin D and calcium. If the intake of these elements from food is insufficient, nutritional supplements are prescribed.

If hypocalcemia develops, appropriate correction of serum calcium levels is carried out.

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

In rare cases, patients receiving bisphosphonates (including Bondronate) develop osteonecrosis of the jaw. Risk factors include an established diagnosis of cancer, concomitant therapy (corticosteroids, radiation and chemotherapy), as well as other disorders such as infections, anemia, coagulopathy, dental diseases. More often, this complication occurs when the drug is administered intravenously, but isolated cases are also known when taking tablets orally.

Manifestations of osteonecrosis of the jaw can be enhanced by dental surgery during bisphosphonate therapy. Whether the risk of osteonecrosis decreases when therapy is discontinued is unknown. The decision to carry out treatment in each case is made individually by the doctor, taking into account the balance of benefit and risk.

No studies have been conducted on the effect of Bondronat on the ability to drive vehicles and operate complex machinery.

Concentrate for the preparation of solution for infusion

The solution prepared from the concentrate should only be administered intravenously. Accidental intra-arterial administration of the drug and its entry into surrounding tissues should be avoided to prevent their damage.

To avoid potential incompatibility, only 0.9% sodium chloride solution or 5% dextrose solution can be used for dilution.

Bondronat should not be mixed with solutions containing calcium.

Film-coated tablets

When taking bisphosphonates orally, local irritation of the mucous membrane of the upper gastrointestinal tract (GIT) and worsening of the course of concomitant diseases of the digestive system are possible. In this regard, caution should be exercised when prescribing the drug to patients with active pathological processes in the upper gastrointestinal tract, such as peptic ulcer, duodenitis, gastritis, dysphagia, Barrett's esophagus, etc.

Cases of esophagitis, esophageal erosions and ulcers, sometimes accompanied by bleeding or further development of strictures or perforations of the esophagus, have been described. In some cases, severe events occurred that required hospitalization. The risk of developing side effects from the gastrointestinal tract is presumably increased in patients who do not adhere to the recommendations for the use of the drug and/or continue to take tablets after the onset of symptoms indicating irritation of the esophagus. For this reason, patients should carefully read the instructions for taking Bondronat and strictly follow them, and if adverse reactions occur in the esophagus, stop taking the drug and consult a doctor. Such symptoms include pain when swallowing or behind the sternum, the appearance of dysphagia, and increased heartburn.

Due to the fact that nonsteroidal anti-inflammatory drugs themselves are associated with gastrointestinal irritation, special caution should be exercised when using them simultaneously with Bondronat.

Special instructions for the use of the drug Bondronat

Tablets Use the drug with caution when creatinine clearance is ≤30 ml/min, as well as in case of hypersensitivity to other bisphosphonates and in combination with NSAIDs. Before starting treatment with Bondronat, hypocalcemia and other disorders of bone metabolism and electrolyte balance should be corrected. It is important to get enough calcium and vitamin D. Taking bisphosphonates can cause dysphagia, esophagitis, and gastric or esophageal ulcers. Therefore, patients should pay special attention to following dosing recommendations. If signs or symptoms of possible damage to the esophagus appear (swallowing problems, pain when swallowing, chest pain, heartburn), you should stop taking the drug. During treatment, it is necessary to monitor renal function, serum calcium, phosphorus and magnesium levels. Concentrate for the preparation of infusion solution The drug is administered only intravenously, it cannot be administered intravenously. Avoid getting the drug solution into surrounding tissues. Bondronate can only be diluted in 500 ml of 0.9% sodium chloride solution or 500 ml of 5% dextrose solution; the drug cannot be diluted in saline solutions. Excessive hydration should be avoided in patients at risk for circulatory failure. Clinical studies of the effect of the drug on the ability to drive vehicles or operate potentially dangerous mechanisms have not been conducted. Cases of osteonecrosis of the jaw bones have been reported with the use of bisphosphonates. Most cases were recorded in patients with a tumor who underwent dental procedures, but in some cases osteonecrosis was noted in patients with postmenopausal osteoporosis or other diseases. Known risk factors for osteonecrosis of the jaw bones include tumor disease, concomitant therapy (chemotherapy, radiation therapy, corticosteroids), concomitant diseases (anemia, coagulopathy, infections, previous dental diseases). Most cases were observed in patients using IV bisphosphonates, but some cases occurred in patients using oral bisphosphonates. Dental surgery in patients who develop osteonecrosis of the jaw while on bisphosphonate therapy may complicate the course of osteonecrosis. It is not known whether discontinuation of bisphosphonate therapy reduces the risk of osteonecrosis of the jaw in individuals undergoing dental procedures. In each case, the decision should be made based on an individual assessment of the benefit/risk ratio. Pregnancy and breastfeeding There is no clinical experience with the use of Bondronat in pregnant women. It is not known whether Bondronate passes into breast milk. Therefore, it is not recommended to use the drug during pregnancy and breastfeeding. Elderly persons No dose adjustment is required in elderly persons. Children. The safety and effectiveness of Bondronat in patients under 18 years of age has not been established.

Drug interactions

The development of clinically significant drug interactions with the simultaneous use of other drugs is unlikely.

When Bondronate was administered intravenously to healthy volunteers and postmenopausal patients receiving ranitidine, the bioavailability of ibandronic acid increased by 20%, which was probably caused by a decrease in gastric acidity.

The absorption of Bondronat tablets can be disrupted by foods containing calcium and other polyvalent cations (for example, iron, magnesium, aluminum), including solid food and milk, so they can be consumed at least 30 minutes after taking the drug.

Drug interactions Bondronat

Interactions with food Food products containing calcium and other polyvalent cations (aluminum, magnesium, iron), including milk and food additives, may interfere with the absorption of the drug, so they should be consumed no earlier than 30 minutes after taking Bondronat. Interaction with other drugs Calcium preparations, antacids and some other oral drugs that contain polyvalent cations (aluminum, magnesium, iron) may interfere with the absorption of Bondronat. Therefore, the interval between taking Bondronat and other oral medications should be at least 30 minutes. Pharmacokinetic interaction studies in the postmenopausal period demonstrated the absence of any interaction with tamoxifen or hormone replacement therapy (estrogens). No interaction was observed when taken concomitantly with melphalan/prednisolone in patients with multiple myeloma. Ranitidine, when administered intravenously, increases the bioavailability of ibandronic acid by approximately 20%. No dose adjustment of Bondronat is required when used concomitantly with H2 receptor blockers or other drugs that reduce gastric acidity. Ibandronic acid does not affect cytochrome P450 isoenzymes. Binding to plasma proteins when using the drug is insignificant. Ibandronic acid is eliminated by renal excretion and does not undergo biotransformation. The elimination pathway of ibandronic acid does not include any transport systems involved in the elimination of other drugs.