Expiration date: 02/2026

The composition and form of issue: 

Powder for suspension preparation for intake. 1 sachet contains:

strontium ranelate 2 g

excipients: aspartame, maltodextrin, mannitol 

in sachets of 2 g in cartons of 7, 14, 28, 56, 84 or 100 sachets.

Description pharmaceutical form:

Powder from white to pale yellow.

By dissolving the powder in water formed an opaque white slurry.

Pharmacokinetics:

The composition of the medicinal formula of strontium ranelate contains two atoms of stable strontium and one molecule danilovoy acids (organic part, which helps them achieve desired values of molecular weight, provides favorable pharmacokinetic properties and good tolerability drugs). The pharmacokinetics of strontium and danilovoy acid was estimated in the group of healthy young men and healthy postmenopausal women, as well as during prolonged use of the drug in the group of women with osteoporosis in postmenopausal women, including older women.

Absorption, distribution and binding danilovoy acid to plasma proteins are quite low, due to the high polarity of the molecule.

Rangelova acid accumulates and does not show metabolic activity in the body of animals and humans.

Rangelova acid is absorbed rapidly and unchanged excreted from the human body by the kidneys.

Absorption

The absolute bioavailability of strontium after oral administration of 2 g of strontium ranelate is about 25% (19-27%). Cmax in plasma is reached after 3-5 h after a single intake of 2 g of the drug. Css achieved after 2 weeks of therapy. The intake of strontium ranelate with food, food additives and calcium supplementation reduces the bioavailability of strontium by approximately 60-70% compared to the level of bioavailability when the drug is after 3 hours after a meal. Taking into account the relatively slow absorption of strontium, one should avoid foods, medications and supplements calcium before and after administration of the drug Bivalos. Drugs and food supplements of vitamin D do not exert any influence on the absorption of strontium.

Distribution

Vd strontium is about 1 l/kg. Binding of strontium from human plasma protein is low (25%), while strontium is characterized by high affinity for bone tissue. Measurement of strontium concentration in iliac bone biopsies of patients treated with strontium ranelate at a dose of 2 g/day for a long time (up to 60 months), suggests that the concentration of strontium in the bone tissue reaches a plateau after about 3 years of therapy. Data for elimination of strontium from bone after cessation of therapy do not exist.

Biotransformation

Representing a divalent cation, strontium is not metabolized in the human body. Strontium ranelate does not inhibit enzymes of the cytochrome P450.

Elimination

Elimination of strontium is time and dose dependent. Effective T1/2 strontium is approximately 60 h. the Strontium excreted by the kidneys and through the digestive tract. Plasma clearance of strontium is about 12 ml/min (CV 22%) and renal clearance about 7 ml/min (CV 28%).

Pharmacokinetics in special patient groups

Patients of advanced age. Data on the pharmacokinetics in the target population indicate a lack of relationship between age and determined by the clearance of strontium.

Patients with renal insufficiency. In patients with renal insufficiency mild to moderate degree (Cl creatinine 30-70 ml/min), strontium clearance decreases as creatinine Cl reduction (about 30% at the values Cl creatinine in the range of 30 to 70 ml/min), which leads to an increase in the plasma concentration of strontium. In clinical studies, 85% of patients with Cl creatinine ranged from 30 to 70 ml/min, and 6% — <30 ml/min at the time of inclusion, while the average value of Cl creatinine was about 50 ml/min. Thus, dosage adjustment in patients with mild to moderate renal impairment is not required. Data on the pharmacokinetics of the drug in patients with severe renal insufficiency (Cl creatinine <30 ml/min) are absent.

Patients with hepatic insufficiency. Data on the pharmacokinetics of the drug in patients with hepatic insufficiency are absent. However, given the pharmacokinetic properties of strontium, we can assume that they are not affected in this group of patients.

Description pharmacological action:

In vitro studies of strontium ranelate stimulates bone formation in culture of bone tissue and stimulates the replication of the precursors of osteoblasts and collagen synthesis in bone cell culture, reduces bone resorption by inhibiting the differentiation of osteoclasts and their resorptive activity.

As a result of action of the drug, the balance between formation and destruction of bone tissue changes in the direction of the processes of bone formation.

Activity of strontium ranelate was studied in experiments using various preclinical models. In particular, in experiments on intact rats, application of strontium ranelate resulted in increased trabecular bone mass, trabeculae number and thickness, resulting in improved mechanical properties of the bone.

In bone tissue of human and experimental animals which received the drug, strontium ranelate was mainly absorbirovanija on the surface of the crystals hydroxyappatite and only to a small extent replaced the calcium in these crystals in newly formed bone tissue. Strontium ranelate does not modify the characteristics of the crystals of bone tissue. According to biopsies of the iliac crest carried out after treatment with strontium ranelate at a dose of 2 g/day duration up to 60 months in clinical studies, adverse effects on bone quality or mineralization has not been established.

The combined effects of strontium distribution in bone (see "Pharmacokinetics") and increased absorption of x-rays by strontium compared to calcium leads to the increase of mineral bone density (BMD), measured by the method of two-photon x-ray absorptiometry. Received to date data indicate that these factors contribute to approximately 50% of growth BMD after 3 years of treatment Bivalos at a dose of 2 g/day. This feature should be considered when interpreting changes increased BMD in the course of drug treatment Bivalos.

In studies that have confirmed the ability of the drug Bivalos to reduce the risk of fractures, the measured average value of BMD was increased in the group of patients receiving the drug Bivalos, compared to the original value — for lumbar vertebrae by approximately 4% per year, and for the femoral neck by 2% per year after 3 years increase in BMD amounted to 13-15% and 5-6%, respectively, according to various studies.

Starting from the third month of therapy, and within 3 years of observation there was an increase in biochemical markers of bone formation (bone alkaline phosphatase and C-terminal propeptide of procollagen type I) and the reduction of markers of bone resorption (piperacetazine C-terminal and N-terminal telopeptide in the urine) compared to placebo.

For strontium ranelate for the secondary effect relative to the main pharmacological properties is a slight decrease in serum concentrations of calcium and parathyroid hormone, and increasing the concentration of phosphorus in the blood and the activity of total alkaline phosphatase, which, however, is not accompanied by any clinical effects.

Risk factors of postmenopausal osteoporosis are reduced bone mass, reduced BMD, early menopause, a history of Smoking and family history of osteoporosis.

One of the most clinically significant complications of osteoporosis is the development of fractures, with the risk of fractures increases with the number of risk factors.

Treatment of postmenopausal osteoporosis

During studies involving more than 6.5 thousand postmenopausal women with documented osteoporosis, we studied the effect of the drug Bivalos to prevent fractures.

It was shown that the use of the drug Bivalos reduced the relative risk of new vertebral fractures by 41% after 3 years therapy. This effect became statistically significant starting from the first year of therapy. The relative risk of vertebral fractures, accompanied by clinical symptoms (defined as fractures with the development of pain and/or reducing the growth of the patient not less than 1 cm) was decreased by 38%. Also, the therapy with Bivalos compared with placebo significantly reduced the number of patients whose height has decreased by 1 cm or more. The beneficial effect of the drug Bivalos compared to placebo was demonstrated in the evaluation of quality of life using a special scale QUALIOST and General perception of health in General SF-36.

Confirmed the effectiveness of the drug Bivalos in reducing the risk of new vertebral fractures, including in patients who had no history of fractures related to osteoporosis.

The retrospective analysis showed that patients with no history of fractures and increased BMD of the lumbar spine and/or neck of the femur, which demonstrated osteopenia, drug Bivalos for 3 years reduced the risk of first vertebral fracture by 72%.

In the group of patients with high fracture risk (the value of T-index score of BMD of the femoral neck within &le3) at the age of 74 years, the drug Bivalos for 3 years reduced the risk of femur fractures by 36% in comparison with the group of patients treated with placebo.

Treatment of osteoporosis in men

Efficacy of the drug Bivalos for the treatment of osteoporosis in men has been demonstrated in the course of the 2-year clinical study involving 243 patients with high risk of fractures (mean age of patients was 72.7 years, mean T-score increased BMD of the lumbar spine — 2.6 to 28% with vertebral fractures in history).

In the study, patients received calcium (1000 mg/day) and vitamin D (800 IU/day).

A statistically significant increase in BMD was observed 6 months after initiation of therapy (compared with placebo).

After 12 months of therapy with the drug Bivalos shown a statistically significant increase in average BMD of the lumbar spine (the main criterion of efficiency of 5.32%, p <0.001), similar values were observed during studies of the drug Bivalos to prevent fractures in postmenopausal women.

A statistically significant increase in BMD of the femoral neck and femur BMD index (p <0.001) was observed after 12 months after initiation of therapy drug Bivalos.

Indications:

• treatment of osteoporosis in women in postmenopausal period with the aim of reducing the risk of vertebral fractures and femur (including hip fracture)
  
• treatment of osteoporosis in men to reduce fracture risk.
  

Contraindications:

• known hypersensitivity to strontium ranelate and/or any component of the drug
  
• children up to age 18 years (due to the lack of data on the application).
  
• With caution: in patients with severe renal insufficiency (Cl creatinine <30 ml/min) in patients with an increased risk of developing venous thromboembolism (VTE), including episodes from a history of VTE.
  

Application of pregnancy and breast-feeding:

Drug Bivalos is intended only for the treatment of women in post-menopausal.

Clinical data on the use of strontium ranelate during pregnancy do not exist.

There has been no exposure to the drug Bivalos on the reproductive function in animal studies.

In animal experiments the appointment of strontium ranelate at high doses in pregnancy has led to the development of reversible bone deformities in the offspring.

In the event of pregnancy while taking the drug Bivalos treatment should be terminated immediately.

Strontium is excreted in breast milk. Drug Bivalos should not be administered to nursing women.

Side effects:

The safety of the drug Bivalos studied in clinical trials involving approximately 8,000 patients.

The safety of the drug has been confirmed in the course of the studies involving women with postmenopausal osteoporosis, who were taking long-term (the duration of treatment was 60 months) strontium ranelate at a dose of 2 g/day, the average age of patients at the time of inclusion in the study was 75 years, 23% of patients were aged 80 to 100 years.

The overall frequency of adverse reactions in the appointment of strontium ranelate did not differ significantly from that in the group of patients treated with placebo, while adverse reactions of the drug, as a rule, were mild and of short duration. The most common adverse events were nausea and diarrhoea, which were mainly noted at the beginning of therapy and subsequently the frequency of these adverse reactions was not significantly different in the groups receiving placebo and strontium ranelate.

The following is a list of adverse reactions noted in clinical trials, whose connection with the appointment of strontium ranelate, at least, cannot be ruled out. Frequency is presented in comparison with the placebo group in terms of the following gradation: very often (>1/10), often (>1/100, <1/10) uncommon (>1/1000, <1/100) rare (>1/10000, <1/1000) very rare (<1/10000), and unknown frequency (frequency cannot be estimated by available data).

CNS: frequently — headache, impaired consciousness, loss of memory, rarely — seizures.

From the circulatory system: often — venous thromboembolism.

From the digestive tract: often — nausea, diarrhea, unformed stools.

The skin and subcutaneous tissue: often — dermatitis, eczema.

Significant differences in the nature of adverse events in patient groups younger and older than 80 years at the time of inclusion in the study were noted.

In clinical studies, it has been shown that the annual incidence of venous thromboembolic complications in the group of patients treated with strontium ranelate, was 0.7% during 5 years of observation with a relative risk of 1.4 (95% CI of 1.0 to 2.0) compared with the placebo group.

The laboratory parameters. Acute transient rises in the concentration of muscle fraction of creatine kinase (CPK), more than 3 times greater than the ULN was observed with a frequency of 1.4 and 0.6% in groups of patients treated with strontium ranelate and placebo, respectively. In most cases, the concentration of formaldehyde alone has returned to normal with continued treatment with the drug Bivalos without changing therapy.

During post-marketing use of the drug were noted following side effects.

Gastrointestinal: unspecified frequency — vomiting abdominal pain lesion of the mucous membrane of the oral cavity, including stomatitis and ulceration of the mucous membrane of the oral cavity.

The skin and subcutaneous tissue: unspecified frequency — dermal hypersensitivity reactions, including rash, pruritus, urticaria, angioedema severe hypersensitivity reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis and drug rash, accompanied by eosinophilia and systemic manifestations (DRESS syndrome) (see "Special instructions") alopecia.

From the side of musculoskeletal system and connective tissue: unspecified frequency — muscle spasm, myalgia, bone pain, arthralgia and pain in extremities.

Psychiatric disorders: frequency unknown confusion.

Hepatobiliary system: unspecified frequency — increase in liver transaminases (in connection with skin hypersensitivity reactions).

General disorders and symptoms: unidentified frequency — peripheral edema, hyperthermia (due to skin hypersensitivity reactions).

On the part of the respiratory system: unspecified frequency — bronchial hyperreactivity.

From the blood and lymphatic system: unspecified frequency — marrow failure, eosinophilia (in Association with skin reactions), lymphadenopathy (in Association with skin reactions).

Drug interactions:

Food, in particular milk and dairy products as well as drugs and dietary supplements containing calcium, can reduce the bioavailability of strontium ranelate by approximately 60-70%. In this regard, the reception of strontium ranelate and these substances must be separated by a period of time not less than 2 h (see "Pharmacokinetics").

Study of the clinical interaction in vivo showed that the appointment of hydroxides of aluminum and magnesium as 2 hours before the appointment or simultaneously with the administration of strontium ranelate causes a slight decrease in the absorption of strontium ranelate (AUC decrease up to 20-25%), while in the appointment antacid drug after 2 h after administration of strontium ranelate absorption rate is almost constant. Thus, antacids should preferably be taken no earlier than 2 h after administration of strontium ranelate. However, in practice this scheme of reception of medicines convenient because strontium ranelate is recommended to take before bedtime. In connection with this permitted simultaneous administration of antacids and of strontium ranelate.

Since molecular complexes that contain divalent cations interact at the level of the digestive tract with antibiotics tetratziklinovogo and quinoline series, the simultaneous use of strontium ranelate and these drugs reduce the absorption of these antibiotics. In this regard, it is also not recommended to take such drugs. To prevent such interactions, the appointment of antibiotics from group tetracyclines or quinolone treatment with strontium ranelate should be suspended.

The combined appointment of strontium ranelate with nutritional supplements or drugs vitamin D of any interaction has not been established.

No clinically significant interactions or increase the level of strontium ranelate in the blood with combined use of strontium ranelate with the following drugs: NSAIDs (including acetylsalicylic acid), anilide (e.g. paracetamol), histamine H2-receptors and proton pump inhibitors, diuretics, cardiac glycosides (including digoxin), organic nitrates and other vasodilators used in heart diseases, CCB, beta-blockers, ACE inhibitors, antagonists of angiotensin II receptor, selective beta2-adrenoceptor agonists, oral anticoagulants, thrombocyte aggregation inhibitors, statins, fibrates and benzodiazepine derivatives.

Method of application and dose:

Inside.

The recommended dose of 2 g/day (the contents of one sachet). Due to the chronic nature of the disease, the drug Bivalos contemplated for a long time.

The drug is recommended to take before bedtime. You can take a horizontal position immediately after taking the drug.

Drug Bivalos should be taken in suspension, which need to pour the powder from the sachet into a glass, add water and mix until a uniform distribution of the powder in water.

Despite the fact that studies have demonstrated the stability of strontium ranelate in suspension for 24 h, the suspension is recommended to eat immediately after cooking.

Due to the fact that food, drugs and dietary supplements of calcium, milk and dairy products can reduce the absorption of strontium ranelate is necessary to take the drug between meals, preferably at bedtime at least 2 hours after eating, drinking milk, dairy products, food additives or calcium supplements (see "Interactions" and "Pharmacokinetics").

Patients taking Bivalos, one must also prescribe medications and/or dietary supplements of calcium and vitamin D if insufficient intake of these substances with food.

Use in elderly patients

Correction of the dose according to age is not required.

The efficacy and safety of the drug Bivalos was studied in patients of various age groups in postmenopausal women (maximum age at inclusion in the study amounted to 100 years).

Use in renal failure

In patients with mild or moderate renal insufficiency (Cl creatinine 30-70 ml/min), dosage adjustment is not required (see "Pharmacokinetics"). Patients with severe renal insufficiency (Cl creatinine <30 ml/min) drug Bivalos should be administered with caution (see "Pharmacokinetics" and "Special instructions").

Use in hepatic insufficiency

As strontium ranelate is not metabolised in the body, dose adjustment of the drug in patients with hepatic impairment is not required.

Use in children and adolescents

The efficacy and safety of drug Bivalos in children and adolescents has not been studied, therefore to assign this drug to patients in this age group is not recommended.

Overdose:

In the study of the use of strontium ranelate in the dose of 4 g/day for 25 days in healthy postmenopausal women was demonstrated a good tolerability.

In cases of overdose during clinical trials (up to 4 g/day with a maximum duration of 147 days) of clinically significant side effects were noted.

To reduce the absorption of the active substance in the gastrointestinal tract, we recommend taking milk or antacids.

In the case of a significant exceeding the recommended dose should induce vomiting to remove unabsorbed active substance.

Special instructions:

In patients with chronic renal failure it is recommended to monitor renal function. With the development of severe renal insufficiency, the question of the continuation of drug treatment, Bivalos must be addressed individually.

In clinical studies there was an increase in the incidence of VTE, including pulmonary embolism (see "Side effects"). The reason for this phenomenon is currently not installed. In the treatment of patients at risk of VTE or patients with possible increased risk of VTE, particular attention should be given to identifying possible symptoms of this complication and to conduct its adequate prophylaxis. It should be borne in mind that the risk of venous thrombosis is increased in patients on bed rest and/or in preparation for surgery.

Strontium affects the results of colorimetric methods for assessment of calcium content in the blood and urine. In this regard, for a more accurate assessment of the concentration of calcium in the blood and urine, should be used such methods, as atomic emission spectrometry with an induction-coupled plasma or atomic absorption spectrometry.

The presence of the drug Bivalos excipients aspartame can cause adverse reactions in patients with phenylketonuria (a rare metabolic disorders).

Treatment with Bivalos should stop with the development of severe allergic reactions.

On the background of drug Bivalos there were cases of severe, in some cases fatal, hypersensitivity reactions, including drug rash in combination with eosinophilia and systemic symptoms (DRESS syndrome) (see "Side effects"). DRESS-syndrome manifested by rash, fever, eosinophilia and systemic symptoms (such as adenopathy, hepatitis, interstitial nephropathy, interstitial lung disease). The time from the beginning of the drug Bivalos to the development of this side effect is usually accounted for 3-6 weeks. In most cases, DRESS-syndrome resolved after discontinuation of the drug and initiation of therapy corticosteroids. The process of resolving this side effect could be long-lasting. There have been cases of recurrence of DRESS syndrome in the abolition of the SCS.

It is necessary to inform patients that if a rash should immediately stop taking the drug Bivalos, do not resume therapy and consult a doctor. Patients that have stopped taking the drug Bivalos due to the development of hypersensitivity reactions should not resume therapy with this drug.

Effects on ability to drive vehicles and perform work requiring high speed mental and physical reactions