Bondronat

General characteristics. Structure:

Active agent: ibandronovy acid of 1 mg (in the form of an ibandronat of sodium of monohydrate of 1.125 mg);

Excipients: sodium chloride – 8.600 mg, acetic acid of 99% – 0.510 mg, acetate sodium trihydrate – 0.204 mg, water for injections.

Pharmacological properties:

Pharmacodynamics. Inhibitor of a bone resorption, nitrogen-containing бисфосфонат. Has specific selection effect on a bone tissue thanks to high affinity to mineral components of a bone. Suppresses activity of osteoclasts, reduces the frequency of skeletal complications at malignant diseases.
Ibandronovy acid reduces an osteoclast - the associated release of growth factors of a tumor, slows down distribution and an invasion of cells of a tumor, shows synergy effect with in vitro taxons. Ibandronovy acid prevents the bone destruction caused by blockade of function of gonads, retinoids, tumoral processes or administration of extracts of tumoral in vivo fabric.
In the doses considerably exceeding pharmacological effective ibandronovy acid does not influence a mineralization of a bone tissue.
At a hypercalcemia the inhibiting effect of ibandronovy acid on the ossifluence induced by a tumor and, in particular, on the hypercalcemia accompanying tumoral process is followed by decrease in level of calcium in blood serum and excretion of calcium with urine. In most cases the content of calcium in blood is normalized within 4-7 days after administration of drug. Time median before repeated increase serumal calcium albumine-korregirovannogo to 3 mmol/l – 18-26 days.
Ibandronovy acid prevents development of new and reduces growth of already available bone metastasises that leads to decrease in frequency of skeletal complications, intensity of a pain syndrome, the need for performing radiation therapy and surgical interventions concerning metastatic process in bones, thereby leading to considerable improvement of quality of life of patients.
Ibandronovy acid дозозависимо inhibits tumoral ossifluence that is defined by means of markers of a bone resorption (a pyrrolidinolean and дезоксипиридинолин).

Pharmacokinetics. Absorption. After oral administration ibandronovy acid is quickly soaked up in upper parts of digestive tract. Time of achievement of the maximum concentration of TCmax of 0.5-2 h (a median - 1 h) after reception on an empty stomach, absolute bioavailability - 0,6%. The concomitant use of food or drinks (except clear water) reduces bioavailability of ibandronovy acid by 90%. The use of food or drinks in 30 min. after reception of ibandronovy acid reduces its bioavailability by 30%. At reception of ibandronovy acid in 60 min. prior to food of significant decrease in bioavailability it is not observed.
Concentration of ibandronovy acid in plasma increases in proportion to a dose entered intravenously (in a dose to 6 mg) or the drug accepted inside (in a dose to 100 mg).
Bioavailability of ibandronovy acid decreases to 75% at its reception in 2 hours after food in this connection the drug Bondronat® in the form of tablets is recommended to be accepted on an empty stomach with the subsequent meal not earlier than in 30 min.

Distribution. After hit in a system blood stream ibandronovy acid quickly communicates in a bone tissue or is removed with urine. The seeming final volume of distribution - 90 l; the amount of drug in a bone tissue, usually, reaches 40-50% of the dose circulating in blood. Communication with proteins of plasma at therapeutic concentration of drug - 87%. Thus, probability of emergence of intermedicinal interaction owing to replacement from communication with proteins rather low.
Metabolism
Animals have no data that ibandronovy acid is metabolized (both at people, and).

Removal. 40-50% of amount of the drug circulating in blood get into a bone tissue and collects in it, the remained drug is removed in not changed look by kidneys. Not soaked up drug after peroral introduction is removed in not changed view with a stake.
The size of the observed seeming final elimination half-life varies in wide limits (10-60 h) and depends on a dose of drug and sensitivity of the analysis. Concentration of drug in blood decreases quickly and reaches 10% from maximum in 3 h later in/in introductions and 8 h after intake.
After 12 months of oral administration by patients with osteoporosis no more than double cumulation of drug in plasma was observed. At in purpose of ibandronovy acid with an interval of 4 weeks within 48 weeks at patients with metastatic damage of bones of system cumulation it is noted.
The general clearance of ibandronovy acid low with average values of 84-160 ml/min. The renal clearance (healthy women have 60 ml/min. in a menopause) causes 50-60% of the general clearance and depends on clearance of creatinine. The difference between the general and renal clearance reflects capture of substance in a bone tissue.

Pharmacokinetics at special groups of patients. The pharmacokinetics and bioavailability of ibandronovy acid does not depend on a floor. Also clinically significant interracial distinctions of distribution of ibandronovy acid at persons of Caucasian and Mongoloid race are not revealed. Rather negroid race of data is not enough.
Patients with a renal failure
Exposure of ibandronovy acid at patients with various renal failures depends on the clearance of creatinine (CC).
At patients with a heavy renal failure (KK <30 ml/min.) after single ibandronovy acid in/in an injection of 2 mg (15-minute infusion) was noted increase in average AUC0-24 by 110% in comparison with healthy volunteers.
After single ibandronovy acid in/in an injection of 6 mg (15-minute infusion) average AUC0-24 was 14% higher at patients with a renal failure of easy severity (average KK=68.1 value of ml/min.) and for 86% at patients with a renal failure of moderate severity (average KK=41.2 value of ml/min.) in comparison with healthy volunteers (average KK=120 value of ml/min.). Average Cmax did not increase at patients with a renal failure of easy severity and increased by 12% at patients with a renal failure of moderate severity. For patients with a renal failure of easy severity (KK> 50 and <80 ml/min.) dose adjustment is not required. For patients with a renal failure of moderate severity (KK> 30 and <50 ml/min.) or with a heavy renal failure (KK <30 ml/min.) with metastatic damage of bones at a breast cancer, when passing the therapy directed against bone complications is necessary drug dose adjustment.
37% of ibandronovy acid are removed from an organism during the standard 4-hour procedure of a hemodialysis.
Patients with an abnormal liver function
Patients with an abnormal liver function have no data on pharmacokinetics of ibandronovy acid. The liver does not play an essential role in clearance of ibandronovy acid which is not metabolized, and is removed through kidneys or communicates in a bone tissue. With an abnormal liver function of dose adjustment it is not required from patients. Besides, in therapeutic concentration ibandronovy acid poorly contacts proteins of a blood plasma (85%) therefore probably that the hypoproteinemia at a serious illness of a liver does not lead to clinically significant increase in concentration of ibandronovy acid in blood.
Advanced age
The studied pharmacokinetic parameters do not depend on age (the multifactorial analysis). It is necessary to consider possible depression of function of kidneys at elderly patients.
Children
Data on use of the drug Bondronat® for persons under 18 are absent.

Indications to use:

Metastatic damage of bones for the purpose of decrease in risk of emergence of a hypercalcemia, pathological changes, reduction of pain, decrease in need for performing radiation therapy at a pain syndrome and threat of changes.
Hypercalcemia at malignant new growths.

Route of administration and doses:

Бондронат® in the form of a concentrate to preparation of solution for infusions it is usually applied in the conditions of a hospital.
Standard mode of dosing
Metastatic damage of bones
6 mg in/in kapelno within not less than 15 min., once in 3-4 weeks.
The concentrate for preparation of solution for infusions should be parted in 100 ml 0.9% of solution of sodium of chloride or 5% of solution of a dextrose.
Hypercalcemia at malignant new growths
Бондронат® it is applied only in the form of 1-2-hour intravenous infusions. A concentrate for preparation of solution for infusions 5% of solution of a dextrose dissolve in 500 ml 0.9% of solution of sodium of chloride or in 500 ml.
Therapy by the drug Bondronat® begin after adequate hydration 0.9% with chloride sodium solution. The dose of drug depends on severity of a hypercalcemia, and also on type of a malignant new growth. As a rule, smaller doses of drug, than to patients with humoral type of a hypercalcemia are required for patients with osteolytic metastasises. In most cases the patient with a heavy hypercalcemia (albumine-korrigirovanny serum calcium> 3 mmol/l or> 12 mg/dl) 4 mg once enter. The patient with a moderate hypercalcemia (albumine-korrigirovanny calcium of serum <3 mmol/l or <12 mg/dl) - 2 mg. The maximum single dose applied in clinical trials - 6 mg, does not lead to strengthening of effect.
In most cases, the increased calcium level in serum is returned to normal values within 7 days. The average time of development of a recurrence of a hypercalcemia (repeated increase in concentration serum calcium albumine-korrigirovannogo more than 3 mmol/l) made 18-19 days at doses of 2 and 4 mg. The average time of development of a recurrence at introduction of 6 mg of drug made 26 days.
The limited number of patients (n=50) received the second infusion owing to a hypercalcemia. At insufficient efficiency or at a hypercalcemia recurrence perhaps repeated introduction.
Concentration calcium albumine-korrigirovannogo in serum (mmol/l) is calculated by a formula:
calcium of serum (mmol/l) – [0.02 x albumine (g/l)] + 0.8
or in mg/dl:
calcium of serum (mg/dl) + 0.8 x [4 – albumine (g/dl)]
In mg/dl it is necessary to make multiplication on 4 for transfer of the values calcium albumine-korrigirovannogo in serum expressed in mmol.
Dosing at special groups of patients
Abnormal liver function
Dose adjustment is not required.
Renal failure
Metastatic damage of bones
At a weak renal failure (clearance of creatinine> 50 and <80 ml/min.) dose adjustment is not required.
To patients with moderately expressed (clearance of creatinine> 30 and <50 ml/min.) or heavy disturbance of kidneys (clearance of creatinine <30 ml/min.) with the metastatic damage of bones caused by a breast cancer it is necessary to carry out therapy against bone complications taking into account the recommendations presented in table 1.

Clearance of creatinine (ml/min.)	Dose/duration infuzii1	Volume infuzii2
> 50 and <80	6 mg / 15 minutes	100 ml
> 30 and <50	6 mg / 1 hour	500 ml
<30	2 mg / 1 hour	500 ml

1) at introduction of 1 times to 3-4 weeks
2) 0.9% solution of sodium chloride or 5% dextrose solution

At patients with KK <50 ml/min. efficiency and safety of 15-minute infusion was not studied.
Advanced age
Dose adjustment is not required.
Children
Safety and efficiency at persons under 18 is not established.

To the application instruction, address and destruction
After preparation infusion solution chemically is also physically stable for 24 hours.
From the microbiological point of view infusion solution for intravenous administration needs to be used immediately. If drug is not used at once, then time and storage conditions of the prepared solution are responsibility of the health worker. It is possible to store the prepared solution no more than 24 hours at a temperature of 2-8 °C if cultivation is carried out in controlled and validirovanny aseptic conditions.
To use a concentrate for preparation of solution for infusions once.
Before use solution needs to be examined on presence of foreign visible particles.
To administer the drug only intravenously.
To part only in 0.9% solution of sodium of chloride or 5% dextrose solution in order to avoid potential incompatibility.
The concentrate for preparation of solution for infusions should not be mixed with solutions, calciferous.
To destroy unused solution.
Hit together with waste of medicines to the environment has to be minimized. Utilization of drug by means of sewage or together with household waste is not allowed. It is necessary to use the installed systems for utilization of medicines.

Features of use:

Бондронат® it is not necessary to apply at children due to the lack of clinical experience.
Prior to therapy by the drug Bondronat® it is necessary to correct a hypocalcemia and other disturbances of metabolism of a bone tissue and electrolytic balance. Patients should use enough calcium and vitamin D.
If the patient receives with food not enough calcium and vitamin D, then it is necessary to accept in addition them in the form of nutritional supplements.
Development of a hypocalcemia is possible. In that case patients should carry out the corresponding correction of level of calcium in serum.
The drug for parenteral use is administered only intravenously. It is necessary to avoid accidental intra arterial administration of drug or hit in surrounding fabrics that can lead to their damage.
In clinical placebos controlled randomized researches with the assistance of patients with metastatic damage of bones at a breast cancer data on a renal failure at long administration of drug of Bondronat® are absent. Despite it, according to clinical assessment of each patient, it is necessary to control function of kidneys, content of serumal calcium, phosphorus and magnesium during treatment.
It is necessary to avoid an overhydratation at patients with risk of development of heart failure.
At purpose of bisfosfonat cases of development of an osteonecrosis of a jaw were seldom noted. The majority of cases is registered at oncological patients during the dental procedures, several cases - at patients with post-menopausal osteoporosis or other diseases. Risk factors of development of an osteonecrosis of a jaw include the established diagnosis of cancer, the accompanying therapy (chemotherapy, radiation therapy, corticosteroids) and other disturbances (anemia, a coagulopathy, an infection, diseases of teeth). The majority of cases is noted at in purpose of bisfosfonat, but separate cases were observed at the patients receiving drugs inside.
Surgical dental intervention against the background of therapy of a bisfosfonatama can strengthen manifestations of an osteonecrosis of a jaw. It is unknown whether reduces risk of emergence of an osteonecrosis cancellation of bisfosfonat at patients in need of holding dental procedures. The decision on performing treatment needs to be made for each patient individually after ratio assessment risk/advantage.

Influence on ability to driving of vehicles and work with cars and mechanisms
Researches on studying of influence of the drug Bondronat® on ability to driving of vehicles or work with cars and mechanisms were not conducted.

Side effects:

For assessment of frequency of undesirable effects the following categories of frequency are used: very often (> 10%); often (> 1%, <10%); infrequently (> 0.1%, <1%); seldom (> 0.01%, <0.1%); very seldom (<0.01% including separate cases).
Treatment of a hypercalcemia at malignant new growths
At intravenous administration of the drug Bondronat® in a dose of 2 and 4 mg for the purpose of treatment of a hypercalcemia at malignant diseases the following undesirable reactions were observed:
from an organism in general: very often – fever.
Treatment of metastatic damage of bones
At intravenous administration of the drug Bondronat® in a dose of 6 mg with a 4-week interval for treatment of metastatic damage of bones the following undesirable reactions were observed:
from an organism in general: often – an adynamy, a grippopodobny syndrome;
from the alimentary system: often – diarrhea;
from a musculoskeletal system: often – a mialgiya;
from a nervous system: often – a headache.
Post-marketing observation
Disturbances from a musculoskeletal system and connecting fabric: very seldom at purpose of ibandronovy acid the jaw osteonecrosis was noted.
Disturbances from organs of sight: at therapy of a bisfosfonatama, including ibandronovy acid, it was reported about inflammatory diseases of eyes, such as an episcleritis, a sclerite and a uveitis. In certain cases, despite the carried-out treatment, recovery occurred only after cancellation of bisfosfonat.

Interaction with other medicines:

Existence of clinically significant medicinal interactions is improbable. Ibandronovy acid is removed only through kidneys and is not exposed to biotransformation. The way of removal of ibandronovy acid does not include any transport systems participating in removal of other drugs. Ibandronovy acid does not inhibit and does not induce (it is shown in researches on rats) activity of the main isoenzymes of system of P450 cytochrome. In therapeutic concentration ibandronovy acid poorly contacts proteins of a blood plasma therefore the possibility of the medicinal interaction caused by replacement of drugs from binding sites with proteins is small.
Signs of intermedicinal interaction at co-administration with Melphalanum/Prednisolonum at patients with a multiple myeloma were not revealed.
In clinical trials purpose of the drug Bondronat® was followed by a concomitant use of various antineoplastic drugs, diuretics, antibiotics and analgetic means without signs of clinically significant interaction.
At in introduction at healthy volunteers and patients in a postmenopause ranitidine increased bioavailability of ibandronovy acid by 20% (however, this value is in limits of normal values of bioavailability of ibandronovy acid) that is possibly caused by decrease in acidity of a gastric juice. Dose adjustment of drug at simultaneous use with the blockers of H2-histamine receptors or other drugs increasing рН a stomach is not required.
Interaction between the drug Bondronat® and Tamoxifenum, replaceable hormonal therapy (therapy by estrogen drugs) at patients in a postmenopause, no.

Contraindications:

Hypersensitivity to ibandronovy acid or other components of drug.
Hypocalcemia.
Children's age (lack of clinical experience).
Pregnancy and period of feeding by a breast.

With care
Hypersensitivity to other bisfosfonata.
Clearance of creatinine less than 50 ml/min.

Pregnancy and period of feeding by a breast
Pregnancy
It is not necessary to apply Bondronat® during pregnancy. During preclinical trials fertility disturbance, and also reduction of quantity of embryos (places of implantation), disturbance of normal process of childbirth was revealed (dystocia). Fetotoksichesky or teratogenic action is not revealed. Increase in frequency of visceral anomalies (a syndrome of narrowing of a lokhanochno-ureteric segment) is revealed.
There is no experience of use of the drug Bondronat® for pregnant women.
Feeding period breast
It is unknown whether Bondronat® with breast milk at women is removed.
In researches on rats existence of a small amount of ibandronovy acid in milk after intravenous administration of drug is revealed.
It is not necessary to apply Bondronat® during feeding by a breast.

Overdose:

Now, there are no messages on acute overdose of the drug Bondronat® at oral administration or intravenous administration.
Specific information on treatment in case of overdose of drug is absent. However at overdose of the drug accepted inside development of the undesirable phenomena, such as is possible: gastric disturbance, heartburn, esophagitis, gastritis or ulcer.
For binding of the drug accepted inside it is necessary to use milk or antacids. Because of risk of irritation of a gullet it is impossible to cause vomiting and it is necessary to remain in the straightened standing position.
Holding standard procedures of a hemodialysis leads to considerable decrease in concentration of ibandronovy acid in a blood plasma.

Storage conditions:

At a temperature not above 30 °C.
The prepared solution for infusions is stable within 24 hours at a temperature of 2-8 °C.
To store in the place, unavailable to children.

Issue conditions:

According to the recipe

Packaging:

Concentrate for preparation of solution for infusions, 2 mg / 2 ml and 6 mg / 6 ml
On 2 ml or 6 ml of drug in the bottle from colourless glass of hydrolytic type 1 (EF) corked by the rubber bung laminated by a film from an etilentetraftoretilen, which is pressed out by an aluminum cap with the torn-off plastic cover.
Each bottle together with the application instruction is placed in a cardboard pack.