BONDRONAT

Active material: Ibandronic acid
When ATH: M05BA06
CCF: Bone resorption inhibitor. Bisfosfonat
ICD-10 codes (testimony): (C) 79.5
When CSF: 16.04.04.03
Manufacturer: F.Hoffmann-La Roche Ltd. (Switzerland)

Pharmaceutical form, composition and packaging

Pills, Film-coated white or nearly white, oblong, Engraved “IT” on one side and “L2” – another.

Excipients: lactose monohydrate, povidone K25, microcrystalline cellulose, krospovydon, stearic acid, silica colloidal anhydrous.

The composition of the shell: Opadry 00А28646 (gipromelloza, Titanium dioxide (E171), talc).

7 PC. – blisters (4) – packs cardboard.
28 PC. – PVDC bottles (1) – packs cardboard.

Concentrate for solution for infusion in the form of a transparent, colorless liquid.

Excipients: sodium chloride, sodium acetate, acetic acid 99%, water d / and.

2 ml – colorless glass vials (1) – packs cardboard.

Concentrate for solution for infusion in the form of a transparent, colorless liquid.

Excipients: sodium chloride, sodium acetate, acetic acid 99%, water d / and.

6 ml – colorless glass vials (1) – packs cardboard.

Pharmacological action

Bone resorption inhibitor, nitrogen-containing bisphosphonate.

Has a specific selective effect on bone tissue due to its high affinity for the mineral components of bone. Suppresses osteoclast activity, 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, exhibits a synergistic effect with taxanes in vitro. Ibandronic acid prevents bone destruction, caused by the blockade sex glands, retinoid, tumor processes or administration of tumor tissue extracts in vivo.

At doses, significantly exceeding pharmacologically effective, ibandronic acid does not affect bone mineralization.

In hypercalcemia, the inhibitory effect of ibandronic acid on tumor-induced osteolysis and, in particular, 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 injection. Median time to re-increase serum albumin-corrected calcium to 3 mmol / l – 18-26 days.

Ibandronic acid prevents the development of new and reduces the growth of existing bone metastases, which leads to a decrease in the incidence of skeletal complications, pain intensity, the need for radiation therapy and surgical interventions for metastatic processes in the bones, thereby leading to a significant improvement in the quality of life of patients.

Ibandronic acid dose-dependently inhibits tumor osteolysis, as determined by bone resorption markers (pyridinoline and deoxypyridinoline).

Pharmacokinetics

Absorption

After intake of ibandronic acid is rapidly absorbed from the upper gastrointestinal divisions. The time to reach C_max 0.5 – 2 no (median – 1 no) After taking prandial. The absolute bioavailability – 0.6%. Simultaneous intake of food or drink (In addition to the pure water) reduces the bioavailability of ibandronova acid 90%. Eating food or drinks through 30 min after taking the drug reduces the bioavailability of ibandronic acid by 30%. When taking ibandronova acid 60 minutes before eating a meaningful decrease bioavailability is not observed.

The plasma concentration of ibandronic acid increases in proportion to the dose administered i.v. (at a dose of 6 mg) or a drug taken orally (at a dose of 100 mg).

The bioavailability of ibandronic acid is reduced to 75% when taken through 2 hours after meals, therefore, Bondronat tablets are recommended to be taken on an empty stomach, followed by a meal no earlier than 30 m.

Distribution

After falling into the bloodstream quickly acid ibandronic binds in the bone or excreted in the urine. The seemingly final V_d – 90 l. Plasma protein binding – 87%.

Metabolism and excretion

Information about, ibandronic acid that is not metabolized.

40-50% quantities of preparation, circulating in the blood, penetrates into bone tissue and accumulates in it, the remaining drug is excreted unchanged in the urine. Unabsorbed drug after oral administration is excreted unchanged in the feces.

Terminal T_1/2 -10-60 no. The concentration of the drug in the blood decreases quickly and reaches 10% from C_max through 3 h after i.v. administration and after 8 hours after ingestion.

With intravenous administration of ibandronic acid at intervals 4 weeks during 48 weeks in patients with metastatic bone lesions, no systemic accumulation was observed.

The total clearance of ibandronova acid 84-160 ml / min. Renal clearance (60 mL/min in healthy women in menopause) determines 50-60% General clearance and depends on QC. The difference between the General and the ground substance capture reflects renal bone.

Pharmacokinetics in special clinical situations

Pharmacokinetics of ibandronova acid is not dependent on sex. There were also no clinically significant interracial differences in the distribution of ibandronic acid in individuals of the Southern European and Asian races. Regarding the Negroid race data are insufficient.

Exposure to ibandronic acid in patients with various renal impairment depends on QC. After a single intravenous injection of ibandronic acid in a dose 6 mg (15-minute infusion) average AUC_0-24 increased to 14% in patients with mild renal impairment (the average QC value is 68.1 ml / min) and 86% in patients with moderate renal impairment (the average QC value is 41.2 ml / min), compared with healthy volunteers (the average QC value is 120 ml / min). Average C_max does not increase in patients with mild renal impairment and increases by 12% in patients with moderate renal impairment. In patients with severe renal impairment (CC<30 ml / min) when taking the drug orally in a dose 10 mg for 21 day concentration of ibandronic acid in blood plasma in 2-3 times higher, than in patients with normal renal function.

37% ibandronic acid is eliminated from the body during a standard 4-hour hemodialysis procedure.

There are no data on the pharmacokinetics of ibandronic acid in patients with impaired liver function.. Liver plays no significant role in clearance ibandronova acid, that is not metabolized, and is excreted by the kidneys or bound in bone tissue. No dosage adjustment is required in patients with impaired liver function.. Besides, at therapeutic concentrations, ibandronic acid weakly binds to plasma proteins (87%), so, probably, that hypoproteinemia in severe liver disease does not lead to a clinically significant increase in the concentration of ibandronic acid in the blood.

Pharmacokinetic parameters examined do not depend on age. Possible decline in renal function in elderly patients should be considered.

Data on the use of Bondronat in younger people 18 missing years.

Testimony

- metastatic bone lesions to reduce the risk of hypercalcemia, pathological fractures, pain reduction, reducing the need for radiation therapy for pain and the risk of fractures;

- Hypercalcemia of malignancy.

Dosage regimen

Bondronate in the form of a concentrate for the preparation of a solution for infusion is usually used in a hospital setting and is administered intravenously over a period of 1-2 no, after preliminary dilution.

The concentrate for preparing a solution for infusion is diluted in 500 ml 0.9% sodium chloride solution or 5% dextrose.

Tablets are taken orally for at least 1 hours before the first meal or liquid of the day (In addition to the pure water) or other drugs and dietary supplements. The tablets should be swallowed whole, with a glass (180-240 ml) clean water while sitting or standing, and don't lie down during 60 min then take the Bondronat. Tablets should not be chewed or sucked due to the possible formation of oropharyngeal ulcerations.. Do not use mineral water with a high calcium content.

At metastatic bone lesions the drug is introduced into / in the drip (during 1-2 no) dose 6 mg 1 once every 3-4 weeks or taken orally in a dose 50 mg 1 time / day, daily.

At metastatic bone lesions breast cancer the drug is introduced into / in the drip (for not less than 15 m) dose 6 mg 1 once every 3-4 of the week. The concentrate for preparing a solution for infusion should be diluted in 100 ml 0.9% sodium chloride solution or 5% dextrose. 15-the minute infusion should only be given to patients with normal or mild renal impairment (CC > 50 ml / min). In Patients with CC< 50 ml / min the effectiveness and safety of the drug with a 15-minute infusion have not been studied.

At hypercalcemia, caused by malignant neoplasms, Bondronate is used only in the form 1-2 hourly IV infusions. Bondronate therapy begins after adequate hydration 0.9% sodium chloride solution. The dose of the drug depends on the severity of hypercalcemia. Patients with severe hypercalcemia (albumin-corrected serum calcium ≥ 3 mmol/l or ≥12 mg/dl) once introduced 4 mg. Patients with moderate hypercalcemia (albumin-corrected serum calcium < 3 mmol / l or <12 mg / dL) – 2 mg. The maximum single dose is 6 mg and does not lead to increased effect.

If the first injection is insufficiently effective or if hypercalcemia recurs, repeated administration is possible..

The concentration of albumin-corrected calcium in serum in mmol/l is calculated using the formula: serum calcium (mmol / l) – [0.02 x albumin(g / l)] + 0.8.

Serum albumin-corrected calcium concentration in mg/dL is calculated using the formula: serum calcium (mg / dL) + 0.8 x [4 – albumin(g / dl)].

Patients with impaired liver function dose adjustment is required.

In appointing the drug inside patients with mild or moderate renal impairment (CC ≥ 30 ml / min ) dose adjustment is required. At CC < 30 ml / min the dose of the drug should be reduced to 50 mg (1 tab.) 1 times / week.

An increase in the systemic concentration of ibandronic acid does not impair the tolerability of the drug when used as in/infusions in patients with renal impairment of varying severity. However, in patients with metastatic bone lesions in breast cancer the following recommendations should be followed:

¹when administered 1 once every 3-4 of the week

²0.9% sodium chloride solution or 5% Dextrose.

Elderly patients dose adjustment is required.

Safety and efficacy have younger people 18 years not installed.

Data on the safety of using Bondronat in tablet form in patients, unable to stand or sit for a period of time 60 minutes after administration, no.

Side effect

The on / in the introduction: fever, asthenia, headache; sometimes – flu-like symptoms (fever, chills, ossalgia and myalgia), which in most cases do not require specific treatment and disappear after a few hours or days), allergic reactions; rarely – dyspepsia, diarrhea, bronchospasm in patients with “aspirin” asthma.

From the laboratory parameters: decreased calcium excretion by the kidneys, gipofosfatemiя, not requiring therapeutic intervention; sometimes – hypocalcemia.

If ingestion: common – dyspepsia and hypocalcemia.

Rarely: osteonecrosis of the jaw.

Contraindications

- Children's age (due to lack of clinical experience);

- Pregnancy;

- Breastfeeding;

- Hypersensitivity to the drug.

FROM caution It should be prescribed the drug for severe impaired renal function (CC < 30 ml / min), with hypersensitivity to other bisphosphonates, if taken orally simultaneously with NSAIDs.

Pregnancy and lactation

The use of the drug Bondronat is contraindicated during pregnancy and lactation.

Cautions

Before starting Bondronat therapy, 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 receives insufficient dietary intake of calcium and vitamin D, You should additionally take them in the form of food supplements.

The drug for parenteral use can only be administered intravenously. Avoid intra-arterial administration or contact with surrounding tissues..

Unlike other bisphosphonates, there is no data on renal dysfunction with long-term use of Bondronate. During treatment should monitor kidney function, contents of serum calcium, phosphorus and magnesium.

When administering Bondronat intravenously, overhydration should be avoided in patients at risk of developing heart failure..

The use of oral bisphosphonates is often associated with swallowing problems, esophagitis and formation of ulcers of esophagus and stomach, therefore, it is necessary to pay special attention to following recommendations for oral administration of the drug.

If signs and symptoms of possible esophageal injury occur (appearance or worsening of dysphagia, pain when swallowing and/or behind the sternum, heartburn) the patient should stop taking Bondronat and consult a doctor.

Considering, that NSAID use is associated with gastrointestinal irritation, Caution must be exercised when prescribing NSAIDs and Bondronat together..

Products, calcium-containing and other polyvalent cations (eg, aluminum, magnesium, iron), incl. milk and solid foods, may interfere with the absorption of Bondronat, they should not be used before, than 30 min after oral administration.

Osteonecrosis of the jaw has rarely been reported when bisphosphonates were prescribed.. Most of the cases registered in cancer patients during dental procedures, several cases – in patients with postmenopauznym osteoporosis or other conditions. Risk factors for osteonekroza jaw include established the diagnosis of cancer, concomitant therapy (chemotherapy, radiation therapy, GCS) and other violations (anemia, coagulopathy, infection, gum disease). The majority of the cases noted in the on/in the appointment of bisphosphonate, but individual cases have been observed in patients, treated with drugs inside.

Surgical dental intervention on bisfosfonatami therapy can strengthen the manifestations of osteonekroza jaw. Unknown, reduces the risk of osteonekroza cancellation of bisphosphonate. The decision about treatment should be taken for each patient individually after assessing the risk/benefit ratio.

Effects on ability to drive vehicles and management mechanisms

Studies examining the effect of Bondronat on the ability to drive vehicles and other potentially hazardous activities (including working with machines and mechanisms) not carried out.

Overdose

There are no reports of acute overdose of Bondronat. If overdose, ingested, possible increase in dyspeptic symptoms, the appearance of heartburn, development of esophagitis, gastritis, gastrointestinal ulcers; toxic effect on the liver and kidneys.

Treatment: calcium gluconate IV, hemodialysis. Milk or antacids should be used to bind the drug taken orally.. Due to the risk of esophageal irritation, do not induce vomiting and must remain in an upright standing position.. Should monitor liver and kidneys.

Drug Interactions

Ibandronic acid is excreted only by the kidneys and does not undergo biotransformation. The elimination route of ibandronic acid does not involve any transport systems, involved in excretion of other drugs. Ibandronic acid has no effect on the activity of the major cytochrome P450 system Isoenzymes.

In therapeutic concentrations ibandronic acid is weakly associated with blood plasma proteins, therefore the possibility of drug interactions, caused by displacement of drugs from protein binding sites, slight.

Bondronat solution is incompatible with calcium-containing solutions.

With the simultaneous use of bisphosphonates and NSAIDs, irritation of the gastrointestinal mucosa is possible.

When administered intravenously, ranitidine increases the bioavailability of ibandronic acid by 20%. Dose adjustments when used concomitantly with H blockers₂-histamine receptors or other drugs, increasing gastric pH, not required.

Bondronat interaction with tamoxifen, Estrogen (during HRT) absent in postmenopausal patients.

Conditions of supply of pharmacies

The drug prescription.

Conditions and terms

Pills, coated, should be stored in a place protected from moisture at a temperature not exceeding 30°C. Shelf life of tablets in bottles – 2 year, blisters – 3 year.

The concentrate for the preparation of solution for infusion should be stored at a temperature not exceeding 30°C. Shelf life – 5 years. The prepared solution for infusion is stable for 24 hours at a temperature of from 2 ° to 8 ° C..

The drug should be stored out of reach of children.