BIVALOS

Active material: Strontium ranelate
When ATH: M05BX03
CCF: Preparation, influencing the metabolism of bone tissue, used for osteoporosis in postmenopausal women
ICD-10 codes (testimony): M81.0, M81.1
When CSF: 16.04.05
PManufacturer: Servier Laboratories (France)

Pharmaceutical form, composition and packaging

Powder for oral suspension yellow color.

Excipients: Aspartame (E951), maltodextrin, mannitol.

2 g – sachet (7) – packs cardboard.
2 g – sachet (14) – packs cardboard.
2 g – sachet (28) – packs cardboard.
2 g – sachet (56) – packs cardboard.
2 g – sachet (84) – packs cardboard.
2 g – sachet (100) – packs cardboard.

Pharmacological action

Preparation, influencing the metabolism of bone tissue.

In in vitro studies show, that strontium ranelat stimulates the formation of bone in bone tissue culture, as well as stimulating Osteoblast predecessors replication and synthesis of collagen in cultured bone cells; reduces bone resorption by suppressing differentiation of osteoclasts, as well as their resorptive activity.

Experimental studies on laboratory animals, the use of strontium ranelate has resulted in increase of trabecular bone mass, number of trabeculae and their thickness, as a result, improved mechanical properties of bone.

The human bone of strontium ranelate after hydroxyapatite crystals on the surface and only marginally zameŝalo calcium in these crystals in the newly formed bone. Strontium ranelat does not change the characteristics of the crystallization of bone tissue. According to the iliac Crest biopsies, received in phase III clinical trials in different time periods (to 60 months) strontium ranelatom treatment dose 2 g / day, any adverse impact on the quality of bone tissue or mineralization has not been.

Combined effects of distribution of strontium in bone tissue and increased, According to radiography, strontium absorption compared with calcium, lead to increased bone mineral density (MPKT), measured by x-ray absorpriometry dvuhfotonnoj. Received to date indicates, that these factors constitute approximately 50% measured MPKT index increase through 3 year of treatment with Bivalos^® dose 2 g / day. This feature should be taken into account when interpreting changes in index MPKT during treatment with Bivalos^®. In clinical studies phase III, confirmed the ability of the Bivalos^® to reduce the likelihood of fractures, measured mean value MPKT grew compared to baseline (in the Group of patients, receiving Bivalos^®) for the lumbar vertebrae approximately 4% in year, and for the femoral head on 2% in year, and reached through 3 year 13-15% and 5-6% respectively (According to various studies).

In clinical studies phase III, starting from the third month to complete monitoring for 3 years, levels of biochemical markers of bone formation (ALP bone tissue and c-Terminal propeptide of type I procollagen) increased compared to placebo, the levels of bone resorption markers (P-telopeptidnye cross-bridges in the serum and N-telopeptidnye cross-bridges in the urine) decreased.

For strontium ranelate secondary effect, in relation to the basic pharmacological properties, is the small decrease serum concentrations of calcium and parathyroid hormone, as well as increasing the concentration of phosphorus in the blood and the activity of the overall AP, that however is not accompanied by any clinical adverse effects.

Clinical efficacy

Osteoporosis is diagnosed by reducing the value of MPKT in the vertebrae or the ball of the femur to the >2.5 standard deviations from the mean value for the populations of healthy young persons. Many risk factors contribute to the development of osteoporosis postmenopauznogo. Among them – reduced bone mass, Special MPKT, early onset of menopause, status of smoking history and family burdenedness on osteoporosis. One of the most clinically significant manifestations of osteoporosis is the development of fractures. The risk of fracture increases with the number of risk factors.

Postmenopauznogo treatment of osteoporosis

Influence of the drug studies program Bivalos^® the tendency to develop fractures included two placebo-controlled clinical studies phase III (SOTI and TROPOS).

The study involved SOTI 1649 postmenopausal women (average age 70 years), had documented osteoporosis (low MPKT index and frequent fractures of vertebrae). TROPOS study observed 5091 postmenopausal women (average age 77 years), had osteoporosis (low MPKT index and thigh fractures in history more than half of the study participants). The total population of SOTI and TROPOS studies included 1556 women with osteoporosis in aged 80 at the time of inclusion in research (23.1% the entire surveyed population). In addition to the therapy of strontium ranelatom dose 2 g/day or placebo, patients in both studies received nutritional supplements of calcium and vitamin D in selected dosages.

SOTI study drug Bivalos^® reduced relative risk of new spinal fractures by 41% through 3 years of therapy (table 1). This effect became a reliable, beginning in the first year of therapy. Similar beneficial effects have been demonstrated in women, on the original stage had multiple fractures in history. With regard to clinically shown fractures of vertebrae (defined as fractures combined with the development of pain and/or reduction in the length of the body is not less than 1 cm) relative risk decreased to 38%. In this regard, drug therapy Bivalos^® reliably reduced the number of patients with a decrease in length not less than 1 see the result of fractures, compared with the placebo group. Evaluation of the quality of life of patients was carried out with the assistance of the ad hoc scale QUALIOST and assess the overall perception of the health of the overall scale of the SF-36, as a result of which has been demonstrated by the favorable influence of the drug Bivalos^® compared to placebo.

Efficacy Bivalos^® on the risk of the development of new vertebral fractures was confirmed in a study of TROPOS, which included patients with osteoporosis without fractures on the original stage.

Table 1. The frequency of fractures of the vertebrae and the magnitude of relative risk reduction

Joint analysis group of patients over the age of 80 at the time of inclusion in research and TROPOS SOTI has demonstrated, drug Bivalos^® reduces the relative risk of new vertebral fractures in 32% for 3 year (the frequency of fractures 19.1% Bivalosa group^® and 26.5% placebo).

When analyzing a-posteriori (based on the experience) in the joint group, participating in research and SOTI TROPOS, whose original stage index MPKT of the lumbar vertebrae and/or femur ranged osteopenia, and that were not prone to frequent fractures, However, there have, at least, one additional risk factor for fractures (n = 176), product Bivalos^® for 3 year of treatment reduced the risk of vertebral fracture at first 72% (the frequency of fractures of the vertebrae was 3.6% the drug group Bivalos^® and 12% placebo).

Analysis of a-posteriori, held in the subgroup of patients, involved in the study TROPOS, represents a special medical interest, Since this category was examined patients at high risk of fractures (that was determined by t-points index MPKT of the femoral head within ≤ 3 standard deviations (SD) /the range of the manufacturer corresponds to ≤ 1.5 SD/the study NHANES III) and it was over 74 years (n = 1 977), what is 40% patients, involved in the study TROPOS. In this group over the 3 years of therapy drug Bivalos^® reduced the risk of hip fractures in the 36%, compared with the placebo group (table 2).

Table 2. The frequency of hip fractures and relative risk reduction in patients with MPKT ≤ 1.5 SD (According to data from NHANES III) at the age of 74 years, ≥

Pharmacokinetics

Composed of the strontium ranelate contains formulas dosage two atoms stable strontium and 1 molecule ranelovoj acid, as well as an organic part of, which achieved the necessary values for the molecular weight, provided with favorable pharmacokinetic properties and good tolerance of the drug. Pharmacokinetics of strontium and ranelovoj acid was evaluated in a group of healthy young men and women in healthy postmenopausal women, as well as during prolonged use of drugs in a group of postmenopausal women with osteoporosis, including older women. Absorption, distribution and ranelovoj acid binding to plasma proteins are quite low, due to the high polarity of molecules. Ranelovaâ acid not koumouliruet and shows no metabolic activity in laboratory animals and human body.

Absorption

After taking the drug inside in one dose 2 г C_max plasma levels achieved after 3-5 no. Absolute bioavailability of strontium is 25% (range 19-27%). Strontium ranelate reception together with calcium and food reduces the bioavailability of strontium by approximately 60-70% compared with bioavailability when taken drugs through 3 hours after meals. Taking into account the relatively slow absorption of strontium, You should not take food and drugs calcium as before, and after applying the product Bivalos^®.

Distribution

The equilibrium state is achieved after 2 weeks of therapy.

V_d is about 1 l / kg. Binding of human plasma proteins by strontium low and is 25%, When the strontium is characterized by high affinity for bone tissue. Measuring concentrations of strontium in the iliac Crest biopsies in patients, receiving strontium ranelat dose 2 g/d for a long time (to 60 Months), show, concentrations of strontium in bone tissue can reach a plateau after about 3 years of therapy. Any data on Elimination of strontium from the bone after cessation of therapy are not available.

Metabolism

Introducing a Divalent Cation, strontium is not metabolized in human body. Strontium ranelat does not inhibit cytochrome P450 system Isoenzymes.

Deduction

Elimination of strontium is time-dose. Effective T_1/2 strontium is approximately 60 no. Strontium is excreted through the kidneys and intestines. Plasma clearance of strontium is around 12 ml / min, renal clearance – about 7 ml / min.

Ranelovaâ acid is rapidly absorbed and excreted unchanged to the kidneys.

Pharmacokinetics in special clinical situations

Defined clearance of strontium does not depend on age.

In patients with renal insufficiency of mild to moderate severity (CC 30-70 ml / min) strontium is the ground decreases as, like dropping QC (reduction of approximately 30% QC values ranging from 30 to 70 ml / min), that leads to increased concentrations of strontium in plasma. In clinical studies phase III in about 85% sick KK was 30-70 ml / min, and approximately 6% – less 30 mL/min at the time of inclusion in research, the average was about QC 50 ml / min. Thus, any dose adjustment in patients with renal insufficiency, mild not required. Data on the pharmacokinetics of the drug in patients with severe renal insufficiency (CC less than 30 ml / min) not available.

Data on the pharmacokinetics of the drug in patients with hepatic insufficiency do not have. Given the pharmacokinetic properties of strontium, We can assume the absence of any strontium ranelate adverse effects on the liver.

Testimony

— treatment of osteoporosis in postmenopausal women period in order to reduce the risk of vertebral and hip fractures.

Dosage regimen

Bivalos^® It is intended only for the treatment of women in postmenopauzne period.

The drug is taken orally. The recommended dose is 2 g / day (1 sachet).

The drug should be taken only in the form of suspension, obtained after mixing the powder in a glass of water. Prepared suspension should be consumed inside immediately after cooking.

In connection with chronic nature of the illness the drug Bivalos^® take a long time.

Because, that milk and milk products can reduce the absorption of strontium ranelate, the drug needs to be taken in between meals, preferably at bedtime, at least through the 2 hours after meals, drinking milk, dairy products and/or nutritional supplements or calcium preparations.

When insufficient flow of dietary calcium and vitamin D to patients, host Bivalos^®, You must additionally appoint these substances as food additives.

Side effect

Product Bivalos^® studied in clinical trials involving approximately 8000 man.

In clinical studies phase III drug safety has been studied for long-term use in the Group of women with osteoporosis in postmenopausal women, When the dose was 2 g / day (n = 3352), placebo (n = 3317), duration of treatment – 60 months. The average age of patients was 75 at the time of inclusion in research, with about 23% participants were aged 80 to 100 years. The overall incidence of side effects in the appointment of strontium ranelate reliably did not differ from placebo, When the side effects of the drug were mild and transient.

The most frequent side effects were nausea and diarrhea, which mostly occurred in the initial phase of therapy and subsequently had no reliable differences in frequency compared to placebo. The main reason for discontinuation was development of nausea (1.3% and 2.2% in the placebo group and the Group of drug Bivalos^® respectively).

The following are adverse reactions, in phase III clinical trials were contacted various probabilities with the admission Bivalosa^®.

The frequency of side effects Bivalosa^® submitted compared a placebo in the form of the following gradation: Often (>10%), often (>1%, <10%), moderately (>0.1%, <1%); rarely (>0.01%, <0.1%); rarely (<0.01%).

CNS: often – headache (3.3% and 2.7%).

In clinical studies phase III was installed, that through 4 year in the Group of patients, receiving Bivalos^®, disorders of the nervous system were observed more frequently than with placebo: disturbances of consciousness (2.6% and 2.1% respectively), memory loss (2.5% and 2.0%) and cramps (0.4% and 0.1%).

From the digestive system: often – nausea (7.1% and 4.6%), diarrhea (7% and 5%), irregular Chair (1% and 0.2%).

Dermatological reactions: often – dermatitis (2.3% and 2%), eczema (1.8% and 1.4%).

When comparing groups of patients under and over 80 at the time of inclusion in any credible study of differences in the nature of side effects between the treatment groups noted.

Cardio-vascular system: results of a phase III clinical study showed, that the annual incidence of venous thromboembolism (VTЭ) through 4 year of treatment Bivalosom^® It was approximately 0.7%, with a relative risk 1.4 (95%, DI 1.0; 2.0), compared to placebo.

From the laboratory parameters: transient sharp rises in the level of CPK musculo-skeletal fraction more than 3 times higher than observed in the VGN 1.4% and 0.6% in groups with the appointment of strontium ranelate versus placebo, respectively.

In most cases, levels of CPK alone returned to normal with continued drug treatment Bivalos^® and do not require any correction therapy.

When postmarketingovom were using the drug side effects.

From the digestive system: neutochnennoy chastotы – vomiting, stomach ache, defeat mucous membranes of the oral cavity, incl. stomatitis and pitting oral mucosa.

Allergic reactions: neutochnennoy chastotы – skin rash, itching, hives, Stevens-Johnson syndrome, angioedema, severe hypersensitivity reactions, incl. drug rash, accompanied by Eosinophilia and systemic manifestations (DRESS syndrome).

On the part of the musculoskeletal system: neutochnennoy chastotы – pain in the bones and muscles, including muscle spasm, mialgiyu, artralgiû and pain in the limbs.

Contraindications

- Pregnancy;

- Lactation (breast-feeding);

-hypersensitivity to strontium ranelatu and/or other components of the drug.

Pregnancy and lactation

The drug is contraindicated in pregnancy and lactation (breast-feeding).

Any clinical data on the effect of strontium ranelate during pregnancy are not available.

If the drug was wrongly appointed during pregnancy, Treatment should be stopped immediately.

Strontium is excreted in breast milk.

IN experimental studies laboratory animals to the appointment of strontium ranelate in high doses during pregnancy results in the development of reversible bone deformities in the offspring of rats and rabbits; When examining the toxicity of different periods of fetal development in the offspring mentioned the development of bones and teeth abnormalities (ie. curvature of the long bones and ribs waviness).

Cautions

In the absence of data on the safety of strontium ranelate in patients with severe renal insufficiency, the drug is not recommended to appoint patients with KK<30 ml / min.

In patients with chronic renal insufficiency the recommended periodic examination of the kidney. In patients with progressive renal insufficiency, severe need to continue treatment with the physician decides individually.

The caution should be applied Bivalos^® in patients with a high risk of VTE (incl. in patients with episodes of VTE in history). In the treatment of patients at risk for VTE, or patients with a possible increase in the risk of VTE, particular attention should be paid to the specific signs and symptoms of VTE, as well as carrying out adequate prevention of complications.

Results of a placebo-controlled phase III clinical studies indicate that, that treatment with Bivalos^® accompanied by increasing annual incidence of VTE, including pulmonary embolism. The reason for this phenomenon is currently not installed.

In patients older dose adjustment is not required.

In patients with renal insufficiency, mild or moderate (KK from 30 to 70 ml / min) correction dose is not required.

Because strontium ranelat not metabolised in the body, any change in dosage in patients with hepatic insufficiency do not require.

Strontium affects results colorimetric methods for evaluating the content of calcium in the blood and urine. In this regard,, for a more accurate evaluation of concentrations of calcium in the blood and urine should use such methods, as atomic emission spectrometry with inductively coupled plasma and atomic absorption spectrometry.

Product Bivalos^® contains a source of phenylalanine, that can lead to undesirable effects in patients with phenylketonuria.

Against the backdrop of the drug Bivalos^® There were cases of heavy development, in some cases, fatal, hypersensitivity reactions, incl. drug rash in conjunction with Eosinophilia and systemic symptoms (DRESS syndrome). DRESS syndrome manifested by rash, fever, Eosinophilia and systemic symptoms (such as adenopatiâ, hepatitis, Interstitial nephropathy, intersticial′noe lung disease). Time from the beginning of the reception of the drug Bivalos^® prior to the development of this side effect, usually, was 3-6 weeks. In most cases, DRESS Syndrome was allowed after the drug and corticosteroid therapy start. The process of resolving this side effect could be a lengthy. There were cases of relapse of DRESS syndrome when you cancel a corticosteroid.

Patients should be informed about what, that with the appearance of the rash should immediately stop taking the drug Bivalos^®, not to resume therapy and consult a physician. Patients, stopped accepting Bivalosa^® due to the development of hypersensitivity reactions, should not reopen this drug therapy.

Use in Pediatrics

Effectiveness and safety of drug Bivalos^® children and adolescents have not been studied. It is not recommended to appoint drug patients in this category.

Effects on ability to drive vehicles and management mechanisms

The drug does not affect the ability to drive and perform work, requiring concentration and high speed psychomotor reactions.

The results of experimental studies

Preclinical studies for security, genotoxicity and the carcinogenic potential demonstrated the absence of any potential danger of strontium ranelate in humans.

Prolonged oral strontium ranelate in high doses in laboratory animals resulted in abnormalities of bones and teeth, that mostly exhibited spontaneous fractures and delayed bone mineralization.. Marked effects have evolved at levels of strontium in bone in 2-3 times higher, than strontium levels in clinical practice, If this change were subjected to involution after cessation of therapy.

Overdose

Symptoms: in clinical studies when exploring long term use Bivalosa^® daily dose 4 g for 25 days in the Group of women with osteoprorozom in postmenopausal women demonstrated good tolerability of the drug. One-time admission preparation in high doses to 11 g in healthy young male volunteers has not been accompanied by the development of any specific symptoms.

In cases of overdose of the drug during clinical trials (to 4 g/d when the maximum duration 147 d) any clinically significant adverse reactions were observed.

Treatment: in order to reduce the absorption of active substances from the stomach recommended reception milk or antacid drugs. In case of overdose expressed (exceeding the recommended dose) You must call artificial vomiting to remove neabsorbirovannogo active substance.

Drug Interactions

Food, in particular, milk and dairy products, as well as medicines, containing calcium, can reduce bioavailability of strontium ranelate for approximately 60-70% (between meals Bivalosa^® and these substances should observe an interval of not less than 2 no). Clinical study in vivo interactions revealed, that the use of aluminium and magnesium hydroxide as per 2 hours before the reception Bivalosa^®, and simultaneously with the admission Bivalosa^®, causes a slight decrease in the absorption of strontium ranelate (The AUC is reduced by 20-25%), while receiving the drug through antacidnogo 2 h after administration Bivalosa^® the level of removals practically does not change. Thus, Antacids should preferably not take previously, than 2 h after administration Bivalosa^®. In practice, however, this medication is not convenient, because the preparation Bivalos^® It is recommended to take at bedtime. In this connection allowed simultaneous antacids and drug Bivalos^®.

Because molecular complexes, containing bivalent cations, communicate at the level tract with tetracycline antibiotics and hinolonovogo series, simultaneous application Bivalosa^® and these drugs leads to a decrease in the absorption of strontium ranelate (simultaneously is not recommended). With a view to preventing such interactions when prescribing antibiotics of tetracycline or quinolone drug treatment Bivalos^® should be suspended.

When combined with nutritional supplements, containing vitamin D, any type of interaction has been established.

During clinical studies in the target population of patients with any signs of clinically meaningful interaction or concomitant increasing levels of strontium in the blood when combined Bivalosa^® the most frequently designated drugs have been detected. Among these drugs have been studied: NSAIDs (including acetylsalicylic acid), anilidy (such as paracetamol), histamine H₂-receptors, proton pump inhibitors, Diuretic, Digoxin and cardiac glycosides, organic nitrates and other vasodilators, used in heart diseases, Calcium channel blockers, beta-blockers, ACE inhibitors, Angiotensin receptor antagonists, selective beta₂-adrenomimetiki, oral anticoagulants, platelet aggregation inhibitors, Statins, Fibrates and derivatives benzodiazepine series.

Conditions of supply of pharmacies

The preparation is available on medical prescription.

Conditions and terms

List B. No special storage conditions requires. Keep out of the reach of children. Shelf life – 3 year. Do not use beyond the expiration date, on the package.