Бивалос®

General characteristics. Structure:

Active agent: strontium of a ranelat hydrate - 2632 mg in terms of strontium ранелат anhydrous - 2000 mg.
Excipients: aspartame of 20 mg, maltodextrin of 400 mg, Mannitolum of 948 mg.
DESCRIPTION
Powder from white till pale yellow color.
At dissolution of powder in water opaque suspension of white color is formed.

Pharmacological properties:

Pharmacodynamics. In the strontium researches in vitro ранелат:
- stimulates formation of a bone in culture of a bone tissue, and also stimulates replication of predecessors of osteoblasts and synthesis of collagen in culture of bone cells;
- reduces a resorption of a bone tissue by suppression of a differentiation of osteoclasts, and also their resorptive activity.
As a result of effect of drug the balance between education and a caries changes towards processes of formation of a bone. Activity of strontium of a ranelat was studied in experiments with use of various preclinical models. In particular, in experiments on intact rats use of strontium of a ranelat led to increase in trabecular mass of a bone, number of trabeculas and
their thickness therefore mechanical properties of a bone improved. In a bone tissue of the person and experimental animals to whom drug was appointed of strontium ранелат, it was generally absorbed on a surface of crystals of a hydroxyapatite and only in insignificant degree replaced calcium in these crystals in a neogenic bone tissue. Strontium ранелат does not change the characteristic of crystals of a bone tissue. According to a biopsy of a crest of the ileal bone which is carried out
after strontium therapy ranelaty in a dose of 2 g a day in clinical trials, adverse influence on quality of a bone tissue or a mineralization it was not established. The combined distribution effects of strontium in a bone tissue (see the section "Pharmacokinetics") and the raised X-ray absorption strontium in comparison with calcium lead to increase in the mineral density of a bone tissue (MDBT) which is measured by method of a two-photon x-ray absorbtsiometriya. The data obtained by the present moment indicate that these factors cause about 50% of a gain of an indicator of MPKT in 3 years of treatment by the drug Bivalos® in a dose of 2 g/days. This feature should be considered at interpretation of change of an indicator of MPKT during treatment by the drug Bivalos®. In the researches which confirmed ability of the drug Bivalos® to reduce risk of changes, the measured MPKT average value increased in group of the patients receiving the drug Bivalos® in comparison with a reference value – for lumbar vertebrae approximately for 4% a year, and for a femur neck for 2% a year; in 3 years increase in an indicator of MPKT made 13-15% and 5-6%, respectively, on
to data of various researches. Since third month of therapy and within 3 years of observation, increase in indicators of biochemical markers of an osteogenesis (bone fraction of an alkaline phosphatase and C-terminal pro-peptide of procollagen I of type) and decrease in indicators of markers of a resorption of a bone tissue (poperechnosvyazanny S-terminal and N-terminal telopeptid in urine) in comparison with placebo was noted. For strontium of a ranelat secondary effect in relation to the main pharmacological properties is insignificant reduction of serumal concentration of calcium and parathyroid hormone, and also increase in concentration of phosphorus in blood and activity of the general alkaline phosphatase that, however, is not followed by any clinical effects. Risk factors of post-menopausal osteoporosis are the reduced bone weight reduced by MPKT, early approach of a menopause, smoking in the anamnesis and family burdeness on osteoporosis. One of the most clinically significant complications of osteoporosis is development of changes, at the same time the risk of developing of fractures increases at increase in number
risk factors. Treatment of post-menopausal osteoporosis during the researches with participation more than 6,5 thousand women in a postmenopause with documentary confirmed osteoporosis was studied effect of the drug Bivalos® on prevention of changes. It was shown that use of the drug Bivalos® reduced relative risk of developing of new fractures of vertebras by 41% in 3 years of therapy. This effect became reliable, since first year of therapy. The relative risk of fractures of the vertebras which were followed by clinical manifestations (decided as changes on development of a pain syndrome and/or reduction of growth of the patient not less than on 1 cm), decreased by 38%. Also therapy by the drug Bivalos® in comparison with placebo authentically reduced number of patients whose growth decreased by 1 cm and more. The beneficial effect of the drug Bivalos® in comparison with placebo was shown also at assessment of quality of life by means of a special scale of QUALIOST® and the general perception of the state of health on the general scale of SF-36. Efficiency of use of the drug Bivalos® concerning decrease in risk of developing of new fractures of vertebras including at the patients who did not have in the anamnesis of the changes connected with osteoporosis is confirmed. In the retrospective analysis it was shown that at patients with absence in the anamnesis
changes and the indicator of MPKT of lumbar vertebrae and/or necks of a femur demonstrating osteosinging, use of the drug Bivalos® within 3 years reduced risk of the first fracture of vertebras by 72%. In group of patients with high risk of changes (value of T-point of the MPKT index of a neck of a femur in limits ≤ 3 WITH) 74 years administration of drug of Bivalos® within 3 years are aged more senior reduced risk of fractures of femur by 36% in comparison with group of the patients receiving placebo.
Treatment of osteoporosis at men
Efficiency of use of the drug Bivalos® for treatment of osteoporosis at men was shown during 2-year-old clinical trial with participation of 243 patients with high risk of developing of fractures (average age of patients made 72,7 years, average value of T-point of an indicator of MPKT of lumbar department of a backbone-2,6; 28% with fractures of vertebras in the anamnesis). During the research patients received calcium (1000 mg/days) and vitamin D (800
ME/days). Statistically significant increase in an indicator of MPKT was noted in 6 months after the beginning of therapy (in comparison with placebo). In 12 months of therapy the drug Bivalos® showed statistically significant increase in an average value of MPKT of lumbar department of a backbone (the main criterion of efficiency of 5,32%; р <0,001), similar values were noted during the researches on studying of effect of the drug Bivalos® on prevention of changes at
women in a postmenopause. Statistically significant increase in an indicator of MPKT of a neck of a femur and the MPKT index of a femur (р <0,001) was noted in 12 months after the beginning of therapy by the drug Bivalos®.

Pharmacokinetics. As a part of a medicinal formula of strontium of a ranelat two atoms of stable strontium and one molecule of ranelovy acid contain (an organic part thanks to which required values of molecular weight are reached, favorable pharmacokinetic properties and good tolerance of medicine are provided). The pharmacokinetics of strontium and ranelovy acid was estimated in group of healthy young men and healthy women in a postmenopause, and also during prolonged use of drug in group of women with osteoporosis in a postmenopause, including women of advanced age. Absorption, distribution and communication of ranelovy acid with proteins of plasma are rather low that is caused by high polarity of a molecule. Ranelovy acid does not kumulirut and does not show metabolic activity in an organism
animals and person. The absorbed ranelovy acid quickly and in not changed look is removed from a human body by kidneys.
Absorption
Absolute bioavailability of strontium after oral administration of 2 g of strontium of a ranelat makes about 25% (19-27%). The maximum concentration in a blood plasma is reached in 3-5 hours after one-time reception of 2 g of drug. Equilibrium concentration is reached in 2 weeks of therapy. Reception of strontium of a ranelat together with food, nutritional supplements and drugs of calcium reduces bioavailability of strontium approximately by 60 - 70% in comparison with bioavailability level at the use of drug in 3 hours after food. In view of rather slow absorption of strontium, it is necessary to avoid meal, drugs and nutritional supplements of calcium both to, and after administration of drug of Bivalos®. Drugs and nutritional supplements of vitamin D do not render what - or influences on strontium absorption.
Distribution
The volume of distribution of strontium makes about 1 l/kg. Communication of strontium with proteins of plasma of the person low (25%), at the same time strontium is characterized by high affinity to a bone tissue. Measurement of concentration of strontium in bioptata of an ileal bone of the patients receiving strontium ранелат in a dose of 2 g/days throughout a long time (up to 60 months), demonstrates that concentration of strontium in a bone tissue reaches the plateau approximately in 3 years of therapy. Data on elimination of strontium from a bone tissue after the termination of therapy are absent.
Biotransformation
Representing a bivalent cation, strontium is not metabolized in a human body. Strontium ранелат does not suppress enzymes of system of P450 cytochrome.
Elimination
Elimination of strontium is time - and dozozavisimy. The effective elimination half-life of strontium makes about 60 hours. Strontium is emitted with kidneys and through digestive tract. The plasma clearance of strontium makes about 12 ml/min. (CV 22%), and renal clearance – about 7 ml/min. (CV 28%).
Pharmacokinetics at special groups of patients
Patients of advanced age
Data on pharmacokinetics in this target population confirm lack of communication between age and the defined clearance of strontium.
Patients with a renal failure
At patients with a renal failure of easy and moderate degree (clearance of creatinine of 30-70 ml/min.) the clearance of strontium decreases in process of decrease in clearance of creatinine (approximately by 30% at values of clearance of creatinine in the range from 30 to 70 ml/min.) that leads to increase of plasma concentration of strontium. In clinical trials at 85% of patients the clearance of creatinine made from 30 to 70 ml/min., and at 6% – less than 30 ml/min. at the time of inclusion, at the same time average value
clearance of creatinine made about 50 ml/min. Thus, dose adjustment of drug with a slight and moderate renal failure is not required from patients.
Data on drug pharmacokinetics at patients with a heavy renal failure (clearance of creatinine less than 30 ml/min.) are absent.
Patients with a liver failure
Data on drug pharmacokinetics at patients with a liver failure are absent.
Nevertheless, considering pharmacokinetic properties of strontium, it is possible to assume that they do not change at this group of patients.

Indications to use:

Treatment of osteoporosis at women in the postmenopause period for the purpose of decrease in risk of fractures of vertebras and a femur (including a hip neck fracture).
Treatment of osteoporosis at men for the purpose of decrease in risk of changes.

Route of administration and doses:

Inside.
The recommended dose makes 2 g (contents of one sachet) a day. Due to the chronic nature of a disease, the drug Bivalos® is supposed to be accepted for a long time. Drug is recommended to be accepted before going to bed. It is possible to accept horizontal position right after administration of drug. The drug Bivalos® should be accepted in the form of suspension for which receiving powder from a sachet needs to be stirred in one glass of water (see the instruction further). To pour out powder from a sachet in a glass;
To add water;
To mix before hypodispersion of powder in water.
In spite of the fact that researches showed stability of strontium of a ranelat in the form of suspension for 24 hours, suspension is recommended to be used inside
at once after preparation.
Because food, drugs and nutritional supplements of calcium, milk and dairy products can reduce absorption of strontium of a ranelat, it is necessary to accept drug in intervals between meals, preferably before going to bed, at least in 2 hours after food, the uses of milk, dairy products, nutritional supplements or drugs of calcium (see the sections "Interaction with Other Medicines and Other Types of Interaction" and "Pharmacokinetics").
The patients accepting Bivalos® need to appoint in addition drugs and/or nutritional supplements of calcium and vitamin D at insufficient intake of these substances with food.
Use for patients of advanced age
Dose adjustment of drug depending on age is not required.
Efficiency and safety of the drug Bivalos® was studied at patients of various age in a postmenopause (the maximum age at inclusion in a research made 100 years).
Use at a renal failure
With a slight or moderate renal failure (clearance of creatinine of 30-70 ml/min.) of dose adjustment of drug it is not required from patients (see the section "Pharmacokinetics"). Patients with a heavy renal failure (clearance of creatinine less than 30 ml/min.) should appoint the drug Bivalos® with care (see the sections "Pharmacokinetics" and "Special Instructions").
Use at a liver failure
As strontium ранелат is not metabolized in an organism, dose adjustment of drug with a liver failure is not required from patients.
Use for children and teenagers
Efficiency and safety of use of the drug Bivalos® for children and teenagers was not studied in this connection patients of this age group are not recommended to appoint this drug.

Features of use:

At patients with a chronic renal failure it is recommended to control function of kidneys. At development of a heavy renal failure the issue of treatment continuation has to be resolved by the drug Bivalos® in an individual order. In clinical trials increase in frequency of development of VTE, including, thromboembolisms of a pulmonary artery was noted (see the section "Side effect"). The reason of this phenomenon is at the moment not established. At treatment of patients from the VTE risk group or patients with possible increase in risk of VTE special attention has to be paid to identification of possible symptoms of this complication, and also performing its adequate prevention. It must be kept in mind that the risk of venous thrombosis is increased at the patients who are on a bed rest and/or by preparation for surgery. Strontium influences results of colorimetric methods of assessment of content of calcium in blood and urine. In this regard, for more exact assessment of concentration of calcium in blood and urine such methods as atomic issue spectrometry with the induction and connected plasma or atomic absorbing spectrometry have to be used. Existence in the excipient drug Bivalos® aspartame can cause undesirable reaction in patients with a fenilketonuriya (seldom found disbolism).
Treatment by the drug Bivalos® should be stopped at development of heavy allergic reactions.
Against the background of use of the drug Bivalos® cases of development of heavy, in some cases fatal, reactions of hypersensitivity, including, medicinal rash in combination with an eosinophilia and system symptoms (DRESS syndrome) were noted (see the section "Side effect"). DRESS syndrome is shown by emergence of rash, fever, an eosinophilia and system symptoms (such as adenopathy, hepatitis, intersticial nephropathy, intersticial disease of lungs). Time from the beginning of administration of drug of Bivalos® before development of this side effect, as a rule, made 3-6 weeks. In most cases DRESS syndrome was resolved after drug withdrawal and the beginning of glucocorticosteroid therapy. Process of permission of this side effect could be long. DRESS syndrome recurrence cases at cancellation of glucocorticosteroids were noted.
It is necessary to inform patients that at emergence of rash it is necessary to stop immediately administration of drug of Bivalos®, not to resume therapy and to see a doctor. The patients who stopped administration of drug of Bivalos® because of development of reactions of hypersensitivity should not resume therapy by this drug. Influence on ability to manage vehicles and to perform the work demanding the increased speed of psychophysical reactions. Does not influence.

Side effects:

Safety of use of the drug Bivalos® was studied in clinical trials with participation about 8000 patients.
Safety of drug is confirmed during a research with participation of women with post-menopausal osteoporosis, is long accepting (duration of treatment reached 60 months) strontium ранелат in a dose of 2 g/days, average age of patients at the time of inclusion in a research made 75 years, 23% of patients were aged from 80 up to 100 years.
The general frequency of side reactions at purpose of strontium of a ranelat authentically did not differ from that in group of the patients receiving placebo, at the same time side reactions of drug, as a rule, were easy and short-term. Nausea and diarrhea which, were generally noted at the beginning of therapy were the most frequent by-effects, and afterwards the frequency of these side reactions authentically did not differ in groups, the receiving placebos and strontium of a ranelat.
Further the list of the side reactions noted in clinical trials which communication with reception of strontium of a ranelat, at least, cannot be excluded is provided. Frequency is presented in comparison with group of placebo in the form of the following gradation: very often (> 1/10); often (> 1/100, <1/10); not often (> 1/1000, <1/100); seldom (> 1/10000, <1/1000); extremely seldom (<1/10000) and unspecified frequency (frequency cannot be counted according to available data).
From the central nervous system:
Often: headache, consciousness disturbance, memory loss.
Infrequently: spasms.
From circulatory system:
Often: venous thromboembolism.
From digestive tract:
Often: nausea, diarrhea, not properly executed chair
From skin and hypodermic fabrics:
Often: dermatitis, eczema.
On character of the undesirable phenomena in groups of patients younger and 80 years at the time of inclusion in a research are more senior than reliable distinctions it was not noted. In clinical trials it was shown that the annual frequency of development of venous tromboembolic episodes in group of the patients receiving strontium ранелат made 0,7% within 5 years of observation at relative risk 1,4 (95% of DI 1,0; 2,0) in comparison with the group receiving placebo.
Laboratory indicators
Tranzitorny acute rises in concentration of muscular fraction of a kreatinfosfokinaza (KFK), more than by 3 times exceeding the upper bound of norm were noted with a frequency of 1,4% and 0,6% in groups of the patients receiving strontium ранелат and placebo, respectively. In most cases concentration of KFK independently was returned to norm at treatment continuation by the drug Bivalos® without therapy change. At post-marketing use of drug the following collateral was noted
effects:
From digestive tract:
Unspecified frequency: vomiting; abdominal pain; damage of a mucous membrane of an oral cavity, including stomatitis and ulceration of a mucous membrane of an oral cavity.
From skin and hypodermic fabrics:
Unspecified frequency: skin reactions of hypersensitivity, including rash, skin itch, small tortoiseshell, Quincke's disease.
Heavy reactions of hypersensitivity, including Stephens-Johnson's syndrome, toxic epidermal necrolysis and the medicinal rash which is followed by an eosinophilia and system manifestations (DRESS syndrome) (see the section "Special Instructions").
Alopecia.
From a musculoskeletal system and connecting fabric:
Unspecified frequency: muscular spasm, mialgiya, ostealgia, arthralgia and extremity pain.
Mental disorders
Unspecified frequency: confusion of consciousness.
Co of the party of gepatobiliarny system:
Unspecified frequency: increase in activity of "hepatic" transaminases (in connection with skin reactions of hypersensitivity).
General frustration and symptoms:
Unspecified frequency: peripheral hypostases, a hyperthermia (in connection with skin reactions of hypersensitivity).
From a respiratory organs:
Unspecified frequency: hyperreactivity of bronchial tubes.
From circulatory and lymphatic system:
Unspecified frequency: insufficiency of marrow, an eosinophilia (in connection with skin reactions of hypersensitivity), a lymphadenopathy (in connection with skin reactions of hypersensitivity).

Interaction with other medicines:

Foodstuff, in particular milk and dairy products, and also medicines and nutritional supplements, calciferous, can reduce bioavailability of strontium of a ranelat approximately by 60-70%. In this regard, reception of strontium of a ranelat and the specified substances has to be divided by a period not less than 2 hours (see the section "Pharmacokinetics"). The research of clinical interaction in vivo showed that purpose of aluminum hydroxides and magnesium both in 2 hours prior to reception, and along with reception of strontium of a ranelat causes insignificant reduction of absorption of strontium of a ranelat (reduction of the square under curve AUC for 20-25%) while at purpose of antiacid drug in 2 hours after reception of strontium of a ranelat absorption level practically does not change. Thus, it is preferable to accept antiacid drugs not earlier than in 2 hours after reception of strontium of a ranelat. However in practice this scheme of drug intake is inconvenient as strontium ранелат it is recommended to accept before going to bed. In this regard, the concomitant use of antiacid drugs and strontium of a ranelat is allowed. As the molecular complexes containing bivalent cations interact at the level of digestive tract with antibiotics
tetracycline and hinolonovy ranks, simultaneous use of strontium of a ranelat and the specified drugs leads to decrease in absorption of these antibiotics. In this regard, it is not recommended to accept at the same time specified medicines. For the purpose of prevention of similar interaction, at prescription of antibiotics from group of tetracyclines or hinolon treatment by strontium ranelaty should be suspended.
At the combined purpose of strontium of a ranelat with nutritional supplements or drugs of vitamin D of any interaction it was not established. Clinically significant interaction or increase in level of strontium of a ranelat in blood at the combined use of strontium of a ranelat with the following medicines is noted: non-steroidal anti-inflammatory drugs (including acetylsalicylic acid), anilides (for example, paracetamol), blockers of H2-of histamine receptors and inhibitors of a proton pomp, diuretics, cardiac glycosides (including, digoxin), the organic nitrates and other vazodilatator applied at heart diseases, blockers of calcium channels, beta adrenoblockers, inhibitors of an angiotensin-converting enzyme, the antagonists of receptors of angiotensin II selection beta-2 by adrenomimetika, peroral anticoagulants, inhibitors of aggregation of thrombocytes, statines, fibrata and derivatives of benzodiazepine.

Contraindications:

The known hypersensitivity to strontium to a ranelat and/or any of drug components.
Children's age up to 18 years (in view of lack of data on use).
With care
At patients with a heavy renal failure (clearance of creatinine less than 30 ml/min.); patients with the increased risk have development of a venous thromboembolism (VTE), including with VTE episodes in the anamnesis.
Pregnancy and period of feeding by a breast
The drug Bivalos® is intended only for treatment of women in the post-menopausal period.
Clinical data on use of strontium of a ranelat during pregnancy are absent.
Impact of the drug Bivalos® on reproductive function in researches on animals was not noted.
In experiments on animals purpose of strontium of a ranelat in high doses during pregnancy led to development of reversible bone deformations in posterity.
In case of pregnancy against the background of administration of drug of Bivalos® treatment has to be immediately stopped.
Strontium is emitted with breast milk. The drug Bivalos® should not be appointed to the women nursing.

Overdose:

When studying use of strontium of a ranelat in a daily dose of 4 g within 25 days in group of healthy women in a postmenopause, good tolerance of drug was shown.
In cases of overdose of drug during clinical trials (to 4 g a day at the maximum duration of 147 days) clinically significant by-effects were not noted. For the purpose of reduction of absorption of active agent in digestive tract reception of milk or antiacid drugs is recommended. In case of considerable exceeding of the recommended dose it is necessary to cause vomiting for removal of not absorbed active agent.

Storage conditions:

Special storage conditions are not required. To store in places, unavailable to children. List B. Period of validity 3 years. Not to apply after a period of validity.

Issue conditions:

According to the recipe

Packaging:

The powder for preparation of suspension for intake containing 2 g of strontium of a ranelat (anhydrous substance).
On 2 g of powder of strontium of a ranelat in a sachet (paper/polyethylene/aluminium/polyethylene). On 7, 14, 28, 56, 84 or 100 sachets with the application instruction in a cardboard pack with control of the first opening.