Bivalos
Bivalos: instructions for use and reviews
- 1. Release form and composition
- 2. Pharmacological properties
- 3. Indications for use
- 4. Contraindications
- 5. Method of application and dosage
- 6. Side effects
- 7. Overdose
- 8. Special instructions
- 9. Application during pregnancy and lactation
- 10. Use in childhood
- 11. In case of impaired renal function
- 12. For violations of liver function
- 13. Use in the elderly
- 14. Drug interactions
- 15. Analogs
- 16. Terms and conditions of storage
- 17. Terms of dispensing from pharmacies
- 18. Reviews
- 19. Price in pharmacies
Latin name: Bivalos
ATX code: M05BX03
Active ingredient: strontium ranelate (strontium ranelate)
Producer: Le Laboratoires Servier Industrie (France)
Description and photo updated: 2018-26-11
Bivalos is a medication that affects bone metabolism and is used to treat osteoporosis.
Release form and composition
Bivalos is produced in the form of a powder for preparation of a suspension for oral administration: loose powder mass of pale yellow or white; the prepared suspension is opaque, white (2 g in a sachet, in a cardboard box 7, 14, 28, 56, 84 or 100 pcs.).
The powder in 1 sachet contains:
- active substance: strontium ranelate hydrate - 2.632 g (corresponds to anhydrous strontium ranelate - 2 g);
- additional components: mannitol, maltodextrin, aspartame.
Pharmacological properties
Pharmacodynamics
In vitro studies have shown that strontium ranelate enhances bone formation in bone culture, as well as the replication of osteoblast precursors and collagen production in bone culture. Also, the active substance of Bivalos, as a result of the inhibition of the differentiation of osteoclasts and a decrease in the resorptive activity of the latter, prevents the resorption of bone tissue. Due to the double effect, the balance between the formation and destruction of bone tissue changes towards osteogenesis (the process of bone formation).
In the course of experimental studies, it was found that under the action of strontium ranelate, the mass of the trabecular bone increased, the number and thickness of trabeculae increased, which led to an increase in bone mass and bone strength.
Clinical and experimental studies have shown that when using Bivalos, its active substance was mostly absorbed on the surface of hydroxyapatite crystals, and in a small amount replaced calcium in these crystals located in the newly formed bone tissue. After taking the drug in a daily dose of 2 g for up to 60 months, no negative effect on bone mineralization or quality was found. Strontium ranelate does not alter the characteristics of bone crystals.
Increases in bone mineral density (BMD) are associated with the combined effects of increased uptake by strontium (as compared to calcium) of X-rays and distribution of matter in bone. When treated with Bivalos in a daily dose of 2 g for 3 years, these factors led to an increase in BMD by approximately 50%.
In the course of clinical studies, in which the ability of the drug to reduce the likelihood of fractures was proven, the average BMD in the group of patients treated with Bivalos increased compared with the baseline value by about 4% per year for the lumbar vertebrae and by 2% for the femoral neck., after 3 years the increase in this indicator reached 13-15% and 5-6%, respectively. Starting from the 3rd month of taking the drug and during 3 years of therapy, there was an increase in the indicators of biochemical markers of the formation of new bone tissue and a decrease in the content of markers of bone resorption when compared with the placebo group.
A burdened hereditary history of osteoporosis, decreased BMD, low bone mass, early menopause, and a history of smoking exacerbate the risk of postmenopausal osteoporosis. One of the most clinically significant complications of the latter is the appearance of fractures, while the threat of their development increases with an increase in the number of risk factors. The effectiveness of Bivalos in preventing fractures has been studied in studies involving over 6,500 postmenopausal women with a confirmed diagnosis of osteoporosis. It was found that the relative risk of new vertebral fractures decreased by 41% after Bivalos therapy for 3 years. This effect of the drug was noted from the 1st year of treatment,the relative risk of vertebral fractures with clinical manifestations (back pain and / or decrease in height by at least 1 cm) decreased by 38%. The use of the product compared with placebo also reduced the incidence of decreased growth by 1 cm or more.
The effectiveness of Bivalos was also confirmed in terms of reducing the threat of new vertebral fractures, including in patients who did not have fractures due to osteoporosis prior to treatment. According to the results of a retrospective analysis, in patients with no history of fractures, but whose BMD of the femoral neck and / or lumbar spine indicated osteopenia, taking the drug for 3 years reduced the risk of a first vertebral fracture by 72%. In patients over 74 years old, with an increased risk of fractures, Bivalos reduced the risk of femoral fractures by 36% over 3 years of admission compared with the placebo group, in patients over 80 years old, the relative risk of new fractures was 32%.
The effectiveness of using Bivalos in the treatment of osteoporosis in men has been proven by the results of a 2-year clinical study. It involved 243 patients with an average age of 72.7 years and a high risk of fractures, with an average T-score (deviation of bone tissue density from the reference value) BMD of the lumbar spine 2.6, of which 28% of participants had instructions in history of vertebral fractures. Patients during the study also took vitamin D at 800 International Units (IU) per day and calcium at 1 g each.
6 months after the start of the course in the group receiving Bivalos, there was a statistically significant increase in BMD in comparison with placebo. After 12 months of therapy, there was a statistically significant increase in the mean BMD of the lumbar spine - the main efficacy rate was 5.32% (similar values were recorded in studies related to the prevention of fractures when using the drug in postmenopausal women). 12 months after the start of treatment, men showed a statistically significant increase in BMD of the femoral neck and BMD index of the femur.
When clarifying the mechanism of action of Bivalos against the background of osteoarthritis during the course of in vitro studies, it was noted that strontium ranelate, influencing human chondrocytes (normal and affected by osteoarthritis), activates the formation of the cartilaginous matrix and inhibits the destruction of cartilaginous tissue, without stimulating cartilage resorption. As a result of the suppression of the production of key resorption factors in the osteoblasts of the subchondral bone, the substance has a positive effect on the pathophysiology of osteoarthritis. In vivo studies have shown that the agent inhibits the occurrence of macrodamage of the upper articular surface of the tibia and femoral condyles, and also reduces the severity of synovitis and sclerosis of the subchondral bone. In clinical trials, treatment with strontium ranelate compared with placebo showed a significant decrease in the content of biochemical markers of cartilage breakdown.
During the three-year use of Bivalos at a dose of 1 or 2 g per day in women and men with clinical primary (idiopathic) osteoarthritis of the knee joint, a slowdown in the progression of this disease compared with placebo was recorded. The amount of narrowing of the inter-articular space (joint space) in the group of patients treated with strontium ranelate in a daily dose of 2 g was 26% less than in the placebo group. It was confirmed by X-ray that the use of Bivalos in a daily dose of 2 g for 3 years provides 1 year of protection against further cartilage degradation. From the first year of using the drug, confirmation of the effectiveness of the treatment was obtained.
In the group of patients taking strontium ranelate 2 g per day, the number of patients with clinically significant progression of cartilage destruction was 23% less than in the placebo group. A slowdown in the narrowing of the knee joint space recorded while taking the drug is associated with a decrease in the severity of osteoarthritis symptoms. In patients with concomitant osteoarthritis of the hip joint, improvement in the function and structure of the knee joint caused by treatment with Bivalos resulted in a decrease in pain in the hip.
Pharmacokinetics
The dosage formula of the active component of Bivalos includes 2 stable strontium atoms and 1 ranelic acid molecule. As an organic part of the compound, ranelic acid ensures the achievement of the required molecular weight values, good tolerance and favorable pharmacokinetic characteristics of the drug. The pharmacokinetics of the two constituents of strontium ranelate was evaluated in a group consisting of healthy young men and healthy women in the postmenopausal period, as well as against the background of long-term use of the drug in a group of women with osteoporosis in postmenopausal women (including the elderly).
Due to the high polarity of the molecule, there is a rather low degree of absorption, distribution and communication of ranelic acid with plasma proteins. This substance does not accumulate in the body and does not differ in metabolic activity. After absorption, ranelic acid is rapidly excreted unchanged by the kidneys.
After oral administration of strontium in a dose of 2 g, its absolute bioavailability can vary from 19 to 27%. The peak concentration of strontium ranelate in the blood plasma is observed 3-5 hours after a single dose of 2 g, the steady-state concentration is reached after 14 days of treatment. The combined intake of the substance with calcium preparations, food and food additives reduces the bioavailability of strontium by an average of 60–70% compared with the use of Bivalos 3 hours after a meal. Given the relatively slow absorption of strontium, it is required to avoid before and after its intake of food, calcium preparations, food additives. Vitamin D preparations do not affect the absorption of the active element.
The volume of distribution of strontium is approximately equal to 1 l / kg, it binds to plasma proteins by 25%, but has a high affinity for bone tissue. According to the measurement results, the strontium content in biopsies of the ilium of patients who took Bivalos for a long period (up to 60 months) in a daily dose of 2 g may reach a plateau after about 3 years of treatment. There are no data on the elimination of strontium from bones after completion of therapy. Being a bivalent cation, the element is not metabolized. Cytochrome P450 enzymes are not inhibited by strontium ranelate.
Elimination of strontium is time- and dose-dependent, with a half-life of approximately 60 hours. Excreted by the kidneys and through the digestive tract, plasma clearance is on average 12 ml / min [coefficient of variation (CV) 22%], and renal clearance is 7 ml / min (CV 28%).
Indications for use
According to the instructions, Bivalos is recommended to be taken to treat the following diseases:
- severe osteoporosis with a high risk of fractures in postmenopausal women, to reduce the risk of vertebral and femoral fractures (including a hip fracture) with intolerance to other drugs for the treatment of osteoporosis or the presence of contraindications to their use;
- severe osteoporosis in men with an increased risk of fractures, in order to reduce it in cases where other drugs for the treatment of osteoporosis cannot be used because of intolerance or the presence of contraindications to their use;
- osteoarthritis of the knee and hip joints, in order to slow down the progress of destruction of cartilage tissue.
Contraindications
Absolute:
- ischemic heart disease (including history);
- uncontrolled arterial hypertension;
- venous thromboembolism (VTE) or a history of VTE episodes, including pulmonary embolism and deep vein thrombosis;
- obliterating lesions of peripheral arteries and / or cerebrovascular diseases (including a history);
- long-term or temporary immobilization (including prolonged bed rest in the postoperative period) in view of the increased risk of venous thrombosis;
- pregnancy and lactation (breastfeeding);
- age up to 18 years;
- hypersensitivity to any of the components of Bivalos.
Relative (you must use the drug with caution):
- increased risk of VTE;
- severe renal failure [creatinine clearance (CC) below 30 ml / min].
Instructions for use of Bivalos: method and dosage
The suspension prepared from the powder is taken orally.
Therapy can only be prescribed by a physician who has experience in treating osteoporosis. The drug is taken in a daily dose of 2 g (contents of one sachet). Since Bivalos is intended for the treatment of diseases of a chronic nature, it is supposed to be used for a long time.
The product is recommended to be used immediately before bedtime. After taking Bivalos, you can immediately take a horizontal position.
To prepare the suspension, the powder from one sachet should be thoroughly mixed with water (⅓ – 1 glass) until it is evenly distributed. Although in the course of studies on the use of the drug it was found that strontium ranelate in the form of a suspension remains stable for 24 hours, it is desirable to take the suspension immediately after preparation.
Since the intake of milk, dairy products and other foods, as well as medications and food supplements of calcium helps to reduce the absorption of strontium ranelate, the latter is recommended to be used at least 2 hours after meals, before bedtime.
Patients with osteoporosis receiving Bivalos need to additionally take vitamin D and calcium supplements in case of insufficient dietary intake.
Side effects
Adverse reactions recorded in clinical trials, the connection of which with the use of Bivalos, at least, cannot be excluded:
- cardiovascular system: often - myocardial infarction [in the presence of postmenopausal osteoporosis in patients taking strontium ranelate (n = 3803) compared with placebo (n = 3769) according to pooled data from randomized placebo-controlled trials];
- circulatory system: often - venous thromboembolism;
- nervous system: often - impaired consciousness, headache, memory loss; infrequently - convulsions;
- skin and subcutaneous tissues: often - eczema, dermatitis; rarely - DRESS syndrome (syndrome of drug-induced hypersensitivity with eosinophilia); extremely rare - severe hypersensitivity reactions (including toxic epidermal necrolysis, Stevens-Johnson syndrome);
- digestive tract: often - diarrhea, nausea, loose stools;
- laboratory indicators: often - an increase in the activity of the muscle fraction of creatine phosphokinase (CPK), exceeding the upper limit of the norm by more than three times, in most cases, these indicators of CPK activity spontaneously returned to normal with further therapy.
Side effects, the occurrence of which has been reported with the post-marketing use of Bivalos (with an unknown frequency):
- musculoskeletal system and connective tissue: myalgia, bone pain, muscle spasm, arthralgia, pain in the limbs;
- skin and subcutaneous tissues: skin hypersensitivity reactions, including itching, rash, urticaria, alopecia, angioedema;
- nervous system: vertigo, dizziness, paresthesia;
- mental disorders: insomnia, confusion;
- digestive system: abdominal pain, vomiting, damage to the oral mucosa, including stomatitis and ulceration of the oral mucosa, dry mouth, dyspepsia, constipation, flatulence, increased activity of hepatic transaminases (associated with skin hypersensitivity reactions), gastroesophageal reflux, hepatitis;
- hematopoietic system and lymphatic system: eosinophilia (caused by skin hypersensitivity reactions), bone marrow insufficiency, lymphadenopathy (caused by skin hypersensitivity reactions);
- respiratory organs: bronchial hyperreactivity;
- general disorders: malaise, hyperthermia (caused by skin hypersensitivity reactions), peripheral edema.
Overdose
When studying the use of strontium ranelate for 25 days at a daily dose of 4 g in healthy postmenopausal women, the drug was well tolerated. A single dose of Bivalos in doses up to 11 g in healthy volunteers did not cause the development of any special disorders.
Against the background of cases of overdose during clinical studies (up to 4 g of Bivalos per day, with a maximum duration of therapy of 147 days), no clinically significant side effects were observed. In order to reduce the absorption of the active substance, it is recommended to take antacids or milk. If a significant overdose is suspected, it is necessary to induce vomiting to remove strontium ranelate, which has not had time to be absorbed.
special instructions
Before starting drug therapy and during its implementation (every 6-12 months), it is required to assess the threat of cardiovascular lesions.
With the development of symptoms of VTE, Bivalos should be stopped immediately.
During the treatment period, cases of severe, life-threatening skin reactions were noted (including Stevens-Johnson syndrome, drug rash accompanied by eosinophilia and the development of systemic symptoms / DRESS syndrome). Patients should be informed about the possible symptoms and signs of these side effects. The threat of developing Stevens-Johnson syndrome is aggravated during the first weeks of therapy, and DRESS syndrome usually occurs 3-6 weeks after the start of the course.
When symptoms / signs of Stevens-Johnson syndrome, toxic epidermal necrolysis (including lesions of the mucous membranes or spreading skin rash, often with blistering), DRESS syndrome (in the form of fever, rash, eosinophilia and systemic symptoms such as hepatitis, adenopathy, interstitial lung damage, interstitial nephropathy), treatment with the drug must be stopped immediately. The best treatment results for such complications were observed with early diagnosis and immediate rejection of any suspicious drug. Usually, DRESS syndrome was resolved when Bivalos was discontinued and glucocorticosteroid (GC) therapy was initiated. The course of the convalescence process can be long, with the cessation of GC treatment, there have been cases of relapse of this severe lesion.
Patients who refuse to use it due to the occurrence of hypersensitivity reactions should not resume taking Bivalos.
It should be borne in mind that strontium ranelate affects the indicators of colorimetric methods for assessing the level of calcium in the blood and urine. As a consequence, in order to more accurately assess its content, it is recommended to use inductively coupled plasma atomic emission spectrometry or atomic absorption spectrometry.
Bivalos contains aspartame, which can cause adverse reactions in patients with phenylketonuria.
Influence on the ability to drive vehicles and complex mechanisms
Bivalos does not affect the ability to drive vehicles and operate complex mechanisms.
Application during pregnancy and lactation
Bivalos therapy is recommended exclusively for postmenopausal women. There are no clinical data on the use of strontium ranelate during pregnancy.
In animal studies, the effect of Bivalos on reproductive function has not been identified. In the case of using high doses of the drug in experiments on animals during their pregnancy, the development of reversible bone deformities was found in the offspring.
If pregnancy occurs during drug therapy, it must be stopped immediately.
Since strontium ranelate passes into breast milk, Bivalos should not be used during breastfeeding.
Pediatric use
For persons under 18 years of age, Bivalos is contraindicated, since the safety profile of strontium ranelate in patients of this age group has not been studied.
With impaired renal function
In patients with mild or moderate functional renal impairment (CC 30–70 ml / min), there is a decrease in strontium clearance as CC decreases (there is a 30% decrease when CC readings are from 30 to 70 ml / min), which is the cause increasing the level of the content of the active substance in the blood plasma. In clinical trials, CC was 30–70 ml / min in approximately 85% of patients at the time of inclusion in the study, and below 30 ml / min in 6%. The average CC value was approximately equal to 50 ml / min. Therefore, in the presence of mild or moderate renal dysfunction, dose adjustment is not required.
In patients with severe renal impairment (CC below 30 ml / min), there is no data on the pharmacokinetics of strontium; therefore, such patients are advised to take Bivalos with caution. Patients with chronic renal failure require periodic monitoring of kidney function. In the event of severe renal failure, the question of continuing to use the drug should be decided on an individual basis.
For violations of liver function
In the presence of liver failure, there is no need for any changes in the dose of the drug, due to the fact that strontium ranelate does not undergo metabolic transformation in the body.
Use in the elderly
It is not required to adjust the dosage of Bivalos in elderly patients, since data on the pharmacokinetics of the drug indicate that there is no relationship between age and the rate of strontium elimination.
Drug interactions
- antacids: a slight decrease in the absorption of strontium ranelate is possible, as a result of which it is preferable to use antacids not earlier than 2 hours after taking Bivalos, but since the latter is desirable to take before bedtime, it is allowed to take strontium ranelate and these funds at the same time;
- antibiotics of the quinolone (ciprofloxacin) and tetracycline (doxycycline) series: a decrease in their absorption was observed, therefore the combined use of strontium ranelate and these drugs is not recommended; if it is necessary to treat with these antibiotics, Bivalos must be stopped;
- anilides (e.g. paracetamol), nonsteroidal anti-inflammatory drugs (including acetylsalicylic acid), histamine H2 receptor blockers, diuretics, proton pump inhibitors, organic nitrates and other vasodilators prescribed for heart disease, cardiac glycosides (including digoxin) angiotensin-converting enzyme inhibitors, beta-blockers, selective beta2-adrenomimetics, calcium channel blockers, angiotensin II receptor antagonists, platelet aggregation inhibitors, oral anticoagulants, fibrates, statins, benzodiazelate derivatives, there was no significant increase in strontium in the blood or interactions these drugs.
Analogs
Bivalos' analogues are: Osteolat, Strometta, Prolia, Osteogenon, Osteokea, etc.
Terms and conditions of storage
Keep out of the reach of children. No special storage conditions are required.
The shelf life is 3 years.
Terms of dispensing from pharmacies
Dispensed by prescription.
Reviews about Bivalos
In most cases, reviews about Bivalos are positive. Patients who received the drug indicate that it helps to restore the normal mineral composition of bone tissue, and is also an effective corrector of cartilage tissue metabolism. According to reviews, the tool demonstrates a very good result in the treatment of fractures against the background of osteoporosis, helping to avoid surgical intervention.
The disadvantages of Bivalos include its high cost, a large list of contraindications and the occurrence of side effects (most often stomach pains).
Price for Bivalos in pharmacies
The price of Bivalos can be 1,850 rubles per package containing 28 sachets of 2 g each.
Anna Kozlova Medical journalist About the author
Education: Rostov State Medical University, specialty "General Medicine".
Information about the drug is generalized, provided for informational purposes only and does not replace the official instructions. Self-medication is hazardous to health!
