Bonnronat - instructions for use, dose, side effects, contraindications

Active substanceIbandronic acidIbandronic acid

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Ibandronic acid Sandoz®

concentrate d / infusion

Sandoz d. Slovenia

Dosage form: & nbspfilm-coated tablets

Composition:

1 tablet contains:

active substance: Ibandronic acid 50 mg (in the form of ibandronate sodium monohydrate 56.25 mg);

Excipients: lactose monohydrate 92.75 mg, povidone K 25 5.0 mg, microcrystalline cellulose 30.0 mg, crospovidone 10.0 mg, stearic acid 95 4.0 mg, silicon dioxide colloid (anhydrous) 2, 0 mg;

sheath: hypromellose, titanium dioxide (E 171), talc - 8.5 mg; macrogol 6000 - 1.5 mg; it is allowed to use the finished mixture Opadriy (Opadry) 00A28646.

Description:Oblong tablets covered with a film coat of white or almost white color; on one side of the tablet the engraving "IT", on the other side - "L2".

Pharmacotherapeutic group:Bone resorption inhibitor-bisphosphonate

ATX: & nbsp

M.05.B.A.06 Ibandronic acid

Pharmacodynamics:

Inhibitor of bone resorption, nitrogen-containing bisphosphonate. It has a specific selective effect on bone tissue due to its high affinity for the mineral components of the bone.Suppresses the activity of osteoclasts, reduces the frequency of skeletal complications in malignant diseases.

Ibandronic acid reduces osteoclast-associated release of tumor growth factor, inhibits proliferation and invasion of tumor cells, exhibits a synergistic effect with taxanes in vitro. Ibandronic acid It prevents bone destruction caused by the blockade of gonadal function, retinoids, tumor processes or by introducing tumor tissue extracts in vivo.

In doses far exceeding the pharmacologically effective, ibandronic acid does not affect the mineralization of bone tissue.

Ibandronic acid prevents the development of new and reduces the growth of existing bone metastases, resulting in a reduction in the frequency of skeletal complications, reduce the intensity of pain and the need for radiotherapy and surgery for metastatic disease in the bones, thus contributing to a significant improvement in patients' quality of life.

Ibandronic acid dose-dependently inhibits tumor osteolysis,which is determined with the help of markers of bone resorption (pyridinoline and deoxypyridinoline).

Pharmacokinetics:

Suction

After oral administration ibandronic acid quickly absorbed in the upper parts of the gastrointestinal tract. Time to reach the maximum concentration TFROM_max 0,5-2 hours (median - 1 hour) after taking an empty stomach, absolute bioavailability - 0,6%. Simultaneous intake of food or drinks (except pure water) reduces the bioavailability of ibandronic acid by 90%. The consumption of food or drinks 30 minutes after the intake of ibandronic acid reduces its bioavailability by 30%. When taking ibandronic acid 60 minutes before eating, a significant reduction in bioavailability is not observed. The concentration of ibandronic acid in plasma increases in proportion to the dose of the ingested drug (at a dose of up to 100 mg) or intravenously administered (at a dose of up to 6 mg). The bioavailability of ibandronic acid is reduced to 75% when it is taken 2 hours after a meal, and therefore the preparation Bondronate® in the form of tablets is recommended to be taken on an empty stomach with a subsequent meal no earlier than 30 minutes.

Distribution

After entering the systemic circulation ibandronic acid quickly binds to bone tissue or is excreted in the urine. The apparent final volume of the distribution is 90 liters; the amount of the drug in the bone tissue usually reaches 40-50% of the circulating dose in the blood. The connection with plasma proteins at therapeutic drug concentrations is 87%. Thus, the probability of the occurrence of inter-drug interaction due to displacement from the bond with proteins is quite low.

Metabolism

Data that ibandronic acid metabolized (both in humans and in animals) no.

Excretion

40-50% of the amount circulating in the blood penetrates into bone tissue and accumulates in it, the remaining drug is excreted unchanged by the kidneys. The non-sucked drug after oral administration is excreted unchanged with feces. The magnitude of the observed apparent final half-life period varies within a wide range (10-60 hours) and depends on the dose of the drug and the sensitivity of the assay. Concentration of the drug in the blood decreases rapidly and reaches 10% of the maximum after 3 hours after IV introduction and 8 hours after ingestion.

After 12 months of oral administration, patients with osteoporosis did not experience more than twice the cumulation of the drug in the plasma.With iv appointment of ibandronic acid at intervals of 4 weeks for 48 weeks, patients with metastatic bones of systemic cumulation were not noted.

The total clearance of ibandronic acid is low, with an average of 84-160 ml / min. The renal clearance (60 ml / min in healthy menopausal women) accounts for 50-60% of the total clearance and depends on the creatinine clearance. The difference between general and renal clearance reflects the capture of matter in bone tissue.

Pharmacokinetics in specific patient groups

The pharmacokinetics and bioavailability of ibandronic acid are independent of sex.

Also, no clinically relevant interracial differences distribution of ibandronic acid in persons of the Caucasoid and Mongoloid race. Relatively Negroid race data is not enough.

Patients with impaired renal function

Exposure of ibandronic acid in patients with various renal dysfunction depends on creatinine clearance (CK).

In patients with severe renal dysfunction (CK <30 ml / min) with oral administration at a dose of 10 mg daily for 21 days, the concentration of ibandronic acid in the blood plasma was 2-3 times higher than in patients with normal renal function (QC≥80 ml / min).Also in patients with severe renal dysfunction, a total clearance of 44 ml / min was observed compared to patients with normal renal function and a total clearance of 129 ml / min.

For patients with impaired renal function of mild severity (QC≥50 and <80 ml / min) dose adjustment for oral administration is not required. For patients with impaired renal function of moderate severity (QC≥30 and <50 ml / min) or with severe renal dysfunction (CK <30 ml / min), dosage adjustment is necessary.

37% of ibandronic acid is excreted during the standard 4-hour hemodialysis procedure.

Patients with impaired hepatic 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 or binds in bone tissue. In patients with impaired liver function, dose adjustment is not required. In addition, in therapeutic concentrations ibandronic acid weakly binds to blood plasma proteins (85%), therefore, it is likely that hypoproteinemia in severe liver disease does not lead to a clinically significant increase in the concentration of ibandronic acid in the blood.

Elderly age

The studied pharmacokinetic parameters do not depend on age (multifactorial analysis). It should be taken into account the possible decrease in kidney function in elderly patients.

Children

Data on the use of Bondronate® in persons under the age of 18 are not available.

Indications:

Metastatic bone damage in order to reduce the risk of hypercalcemia, pathological fractures, reduce pain, reduce the need for radiotherapy with pain syndrome and the threat of fractures.

Contraindications:

Hypersensitivity to ibandronic acid or other components of the drug.

Hypocalcemia.

Lesions of the esophagus, leading to a delay in its emptying, such as stricture or achalasia.

Failure to sit or stand for 60 minutes.

Children's age (lack of clinical experience).

Pregnancy and lactation.

Carefully:

Hypersensitivity to other bisphosphonates. Creatinine clearance less than 50 ml / min.

When ingestion - in combination with non-steroidal anti-inflammatory drugs (NSAIDs).

Pregnancy and lactation:

Pregnancy

Do not use Bonnronate ® during pregnancy.

During preclinical research ibandronic acid caused a violation of fertility, as well as a decrease in the number of embryos (implantation sites), a violation of the normal process of childbirth (dystocia). There was no fetotoxic or teratogenic effect. An increase in the frequency of visceral anomalies (syndrome of constriction of the tuberculosis-ureteral segment) has been found.

Experience in the use of Bondronate ® in pregnant women is not.

Breastfeeding period

It is not known whether Bondronate® is excreted in breast milk in women. In studies on rats, a small amount of ibupronic acid in milk was detected after intravenous administration of the drug. Do not use Bonnronate® during lactation.

Dosing and Administration:

Standard dosing regimen

Inside to 50 mg once a day, daily.

Tablets should be taken orally at least 30 minutes before the first day of this meal of food or liquid (except pure water) or other medicines and food additives (including calcium). Tablets should be swallowed whole, with a glass (180-240 ml) of pure water in a sitting or standing position.Do not lie down for 60 minutes after taking Bonnronate ®. Tablets swallow whole, you can not chew or dissolve because of the possible formation of oropharyngeal ulceration. Tablets should be drunk only with ordinary clean water. Do not use mineral water with a high content of calcium.

Dosing in special patient groups

Bed rest

Studies of the drug for oral administration with the participation of patients incapable of standing or sitting for 60 minutes were not conducted.

Impaired liver function

Correction of the dose is not required.

Impaired renal function

With a mild violation of kidney function (creatinine clearance ≥50 and <80 ml / min) dose adjustment is not required.

With a moderate impairment of kidney function (creatinine clearance ≥30 and <50 ml / min) it is recommended to reduce the dose of the drug to 1 tablet, once every two days.

In case of severe renal dysfunction (creatinine clearance <30 ml / min), the dosage of the drug should be reduced to 1 tablet, once a week.

Elderly age

Correction of the dose is not required.

Children

Safety and efficacy in persons younger than 18 years of age have not been established.

Side effects:

To estimate the frequency of unwanted effects, the following frequency categories are used: very often (≥10%); often (≥1%, <10%); infrequently (≥0.1%, <1%); rarely (≥0.01%, <0.1%); very rarely (<0.01%), including individual cases.

With the oral administration of the drug Bondronate® at a dose of 50 mg daily for the treatment of metastatic bone damage, the following adverse reactions were observed.

Violations from the blood and lymphatic system: infrequently, anemia.

Disorders from the metabolism and nutrition: often - hypocalcemia.

Impaired nervous system: infrequently - paresthesia, dysgeusia (a violation of taste sensations).

Disorders from the gastrointestinal tract: often - esophagitis, abdominal pain, dyspepsia, nausea; infrequently - bleeding, duodenal ulcer, gastritis, dysphagia, dryness of the oral mucosa.

Disturbances from the skin and subcutaneous tissues: infrequently - itchy skin.

Disorders from the kidneys and the urinary tractleading paths: infrequently - azotemia (urmission).

General disorders and disorders at the site of administration: often - asthenia; infrequently - pain in the chest, flu-like syndrome, malaise, pain.

Change in laboratory indicators: infrequently, an increase in the concentration of parathyroid hormone in the blood.

Post-Business Monitoring

Disturbances from the skin and subcutaneous tissues: severe skin undesirable reactions, including Stevens-Johnson syndrome, erythema multiforme and bullous dermatitis.

Disturbances from the musculoskeletal system and connective tissue: rarely - atypical susceptible and diaphyseal fractures of the femur (typical for the bisphosphonate class); very rarely, with the appointment of ibandronic acid, osteonecrosis of the jaw and other maxillofacial areas, including the external auditory canal (see section "Special instructions").

Disturbances on the part of the organ of sight: In the treatment of bisphosphonates, including ibandronic acid, inflammatory diseases of the eye, such as episcleritis, scleritis, and uveitis have been reported. In some cases, despite ongoing treatment, the recovery came only after the removal of bisphosphonates.

Immune system disorders: very rarely - hypersensitivity reactions, angioedema; in the treatment of ibandronic acid, cases of anaphylactic reactions / shock, including fatal, have been reported; allergic reactions,in particular exacerbation of bronchial asthma.

Disturbances from the respiratory system: chest organs and environmentStyles: bronchospasm.

Overdose:

There are currently no reports of an acute overdose of Bondronate® with oral or intravenous administration.

Specific information about treatment in case of drug overdose is absent. However, with an overdose of the drug taken internally, it is possible to develop unwanted phenomena, such as: indigestion, heartburn, esophagitis, gastritis or ulcer. To bind the drug taken orally, use milk or antacids. Because of the risk of irritation of the esophagus, you should not induce vomiting and you must remain in a straightened standing position.

Conducting standard procedures of hemodialysis leads to a significant decrease in the concentration of ibandronic acid in the blood plasma.

Interaction:

Clinically important drug interactions are unlikely.

Ibandronic acid is excreted only through the kidneys and is not biotransformed. The route of excretion of ibandronic acid does not include any transport systems involved in the excretion of other drugs.

Ibandronic acid does not inhibit or induce (as shown in studies on rats) the activity of the main isoenzymes of the cytochrome P450 system.

In therapeutic concentrations ibandronic acid weakly binds to blood plasma proteins, so the possibility of drug interaction due to the displacement of drugs from the binding sites with proteins is small.

Products containing calcium and other polyvalent cations (for example, aluminum, magnesium, iron), including milk and solid foods, can interfere with the absorption of the drug, they should be consumed no earlier than 30 minutes after oral administration of the drug Bondronate®.

There were no signs of inter-drug interaction with concomitant administration with melphalan / prednisolone in patients with multiple myeloma.

In clinical trials, the appointment of the drug Bondronate® was accompanied by the simultaneous administration of various antitumor drugs, diuretics, antibiotics and analgesics without signs of clinically significant interaction.

With intravenous administration in healthy volunteers and patients in postmenopausal women ranitidine increased the bioavailability of ibandronic acid by 20% (however, this value is within the limits of the normal bioavailability of ibandronic acid), which is probably due to a decrease in the acidity of gastric juice.

Correction of the dose of the drug when used simultaneously with blockers H₂-gistaminovyh receptors or other drugs that increase the pH of the stomach, is not required.

The interaction between the drug Bondronate® and tamoxifen, hormone replacement therapy (estrogen therapy) in patients in postmenopausal women, is absent.

Special instructions:

Bondronate® should not be used in children because of lack of clinical experience.

Before starting therapy with the drug Bondronate®, hypocalcemia and other metabolic disorders of bone tissue and electrolyte balance should be corrected. Patients should consume sufficient amounts of calcium and vitamin D. If the patient does not receive calcium and vitamin D with food, then they should additionally be taken as food supplements.

Possible development of hypocalcemia. In this case, patients should make appropriate correction of serum calcium concentration.

The use of oral bisphosphonates can lead to local irritation of the mucosa of the upper gastrointestinal tract. In connection with the possible irritant effect of the drug and worsening of the current underlying gastrointestinal disease, caution should be exercised when prescribing Bonnronic^® 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 oral bisphosphonates, cases of adverse events such as esophagitis, ulcers or erosion of the esophagus, occasionally accompanied by bleeding or the development of strictures or perforations of the esophagus, are described.

In some cases, adverse events were severe and required hospitalization. Probably, the risk of developing severe adverse events on the side of the esophagus is higher in patients who do not follow the dosing regimen and / or continue to take oral bisphosphonates after the appearance of symptoms indicative of esophageal irritation.Patients should carefully read the recommendations for taking the drug and carefully observe them. Doctors should be especially attentiveto any signs or symptoms, indicating that possible reactions from the side of the esophagus, and patients should be warned about the need to stop taking the drug Bondronate ® and see a doctor if they have dysphagia, pain when swallowing or behind the sternum, the appearance or intensification of heartburn.

When using oral bisphosphonates (post-registration observation), individual cases of stomach and duodenal ulcer development, sometimes severe and complicated, are described, although in clinical studies there was no increase in the risk of these diseases.

Since the use of NSAIDs (non-steroidal anti-inflammatory drugs) is associated with irritation of the gastrointestinal tract, caution should be exercised while using NSAIDs with oral administration of the drug Bondronate®.

In clinical placebo-controlled randomized trials involving patients with metastatic bone lesions in breast cancer, data on renal impairment with prolonged use of Bondronate® are not available.Despite this, according to the clinical evaluation of each patient, kidney function, serum calcium, phosphorus and magnesium levels should be monitored during treatment.

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

In the appointment of bisphosphonates, there were rarely cases of osteonecrosis of the jaw. Most cases have been reported in cancer patients during dental procedures, several cases in patients with postmenopausal osteoporosis or other diseases. Risk factors for osteonecrosis of the jaw include an established diagnosis of cancer, concomitanttherapy (chemotherapy, including inhibitors of angiogenesis, radiation therapy, corticosteroids) and other disorders (anemia, coagulopathy, infection, dental diseases). Most cases are noted with the / in the appointment of bisphosphonates, but individual cases have been observed in patients receiving drugs inward.

Surgical dental intervention against the background of bisphosphonate therapy can enhance the manifestations of the osteonecrosis of the jaw.It is unknown whether the risk of osteonecrosis reduces the elimination of bisphosphonates in patients with the need for dental procedures. The decision to conduct treatment should be taken for each patient individually after assessing the risk / benefit ratio.

In patients receiving bisphosphonate therapy, including ibandronic acid, osteonecrosis of other maxillofacial regions, including the external auditory canal, was observed. Additional risk factors may include recurring minor injuries (eg, regular use of cotton buds). The risk factors for osteonecrosis coincided with those in osteonecrosis of the jaw. Patients receiving bisphosphonates and having hearing impairments, including chronic ear infections, should be monitored for osteonecrosis.

Atypical susceptible and diaphyseal fractures of the femur are marked on the background of taking bisphosphonates first of all in patients receiving long-term treatment for osteoporosis. Transverse and short oblique fractures can be localized along the entire length of the femur from a small spit to an epicondylitis elevation.The occurrence of atypical fractures occurs spontaneously or as a result of minor injuries. For weeks or months before the onset of a completed hip fracture Some patients experience pain in hip or in the groin, which is often accompanied by radiographic signs of a stress fracture. Due to the fact that atypical fractures are often bilateral, it is necessary to monitor the condition of another femur in patients with diaphyseal fracture of the femur with bisphosphonate. Poor healing of atypical fractures was noted.

If a suspected atypical fracture is suspected and the results of the survey are obtained, consideration should be given to discontinuing bisphosphonate therapy, based on an assessment of the benefit / risk ratio in each case.

Patients should be informed of the need to report any pain in the thigh or in the groin during therapy with bisphosphonates. If these symptoms are present, a survey should be conducted to identify incomplete hip fracture.

Effect on the ability to drive transp. cf. and fur:

Studies to study the effect of Bondronate® on the ability to drive vehicles or work with machines andmechanisms were not carried out.

Form release / dosage:

Tablets, film-coated, 50 mg.

Packaging:

7 tablets per blister of three-layer film (OPA / Al / PVC) and aluminum foil.

4 blisters together with instructions for use are placed in a cardboard box.

Storage conditions:

At a temperature of no higher than 30 ° C in a dry place.

Keep out of the reach of children.

Shelf life:

5 years.

Do not use after the expiration date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LS-000836

Date of registration:07.06.2010 / 09.07.2013

Expiration Date:Unlimited

The owner of the registration certificate:Hoffmann-La Roche Ltd.Hoffmann-La Roche Ltd. Switzerland

Manufacturer: & nbsp

F.Hoffmann-La Roche, Ltd. Switzerland

Representation: & nbspF.Hoffmann-La Roche Ltd. F.Hoffmann-La Roche Ltd. Switzerland

Information update date: & nbsp14.04.2017

Illustrated instructions

Instructions

Bondronate® (Bondronat® )